Seminar

Myelodysplastic syndromes
Lionel Adès, Raphael Itzykson, Pierre Fenaux

Myelodysplastic syndromes are clonal marrow stem-cell disorders, characterised by ineffective haemopoiesis leading Lancet 2014; 383: 2239–52
to blood cytopenias, and by progression to acute myeloid leukaemia in a third of patients. 15% of cases occur after Published Online
chemotherapy or radiotherapy for a previous cancer; the syndromes are most common in elderly people. The March 21, 2014
http://dx.doi.org/10.1016/
pathophysiology involves cytogenetic changes with or without gene mutations and widespread gene hypermethylation
S0140-6736(13)61901-7
at advanced stages. Clinical manifestations result from cytopenias (anaemia, infection, and bleeding). Diagnosis is
Service d’hématologie, Hôpital
based on examination of blood and bone marrow showing blood cytopenias and hypercellular marrow with dysplasia, St Louis (Assistance Publique
with or without excess of blasts. Prognosis depends largely on the marrow blast percentage, number and extent of Hôpitaux de Paris) and Paris 7
cytopenias, and cytogenetic abnormalities. Treatment of patients with lower-risk myelodysplastic syndromes, University, Paris, France
(L Adès MD, R Itzykson MD,
especially for anaemia, includes growth factors, lenalidomide, and transfusions. Treatment of higher-risk patients is
Prof P Fenaux MD)
with hypomethylating agents and, whenever possible, allogeneic stem-cell transplantation.
Correspondence to:
Prof Pierre Fenaux, Service
Introduction syndromes, acute myeloid leukaemia, or aplastic anaemia. d’hématologie, Hôpital St Louis
Myelodysplastic syndromes are clonal stem-cell Environmental factors include previous use of (Assistance Publique Hôpitaux
disorders predominantly occurring in elderly people. chemotherapy,11 especially of alkylating agents and purine de Paris) and Paris 7 University,
Paris 75475, France
The pathophysiology is a multistep process involving analogues,12,13 radiotherapy,14,15 and tobacco smoking.16 pierre.fenaux@sls.aphp.fr
cytogenetic changes, gene mutations, or both,1 with Recognised occupational factors include exposure to
widespread gene hypermethylation at advanced stages.2–4 benzene and its derivatives,17 and an excess of cases is
The syndromes are characterised by ineffective reported in agricultural and industrial workers.16,18 These
haemopoiesis leading to blood cytopenias and by secondary myelodysplastic syndromes, especially cases
progression to acute myeloid leukaemia in a third of occurring after chemotherapy, generally have poor
patients.5 prognosis as a result of complex cytogenetic findings.
Diagnosis of myelodysplastic syndromes is still based
on examination of the blood and bone marrow, which Biology
shows blood cytopenias and hypercellular marrow with Ineffective haemopoiesis
dysplasia, with or without excess of marrow immature Ineffective haemopoiesis in myelodysplastic syndromes
cells (blasts).6 Prognosis depends mainly on the marrow results from the increased susceptibility of clonal
blast percentage, number and extent of cytopenias, and myeloid progenitors to apoptosis, which leads to
cytogenetic abnormalities.7,8 Treatment, varying from cytopenias despite a generally hypercellular marrow
symptomatic treatment of cytopenias, especially by (figure).19 Progression to acute myeloid leukaemia is
transfusions, to allogeneic stem-cell transplantation, has thought to result from a subsequent shift from
improved in the past few years. apoptosis to proliferation of these clonal progenitors.20,21
In many cases expansion is oligoclonal, rather than
Incidence and cause monoclonal; expansion of minor subclones can also
Myelodysplastic syndromes are generally diseases of older contribute to transformation to acute myeloid
people, with a median age at diagnosis of 65–70 years; less leukaemia.22 Apoptosis of myeloid progenitors can be
than 10% of the patients are younger than 50 years. The triggered by intrinsic factors, such as BCL2-related
disorder shows a slight male predominance except for in proteins,23 for instance resulting from mitochondrial
the form with isolated 5q deletion in which women depolarisation due to iron retention in ringed
predominate.9 The annual incidence of myelodysplastic
syndromes is about four cases per 100 000 people
(reaching 40–50 per 100 000 after age 70 years).9 There are Search strategy and selection criteria
no known ethnic differences in the incidence, but in We searched Medline for articles published from January,
Asian populations the syndromes tend to occur at an 1981, to April, 2013, with the term “myelodysplastic
earlier age, are more likely to include hypocellular marrow, syndrome”. We largely selected publications from the past
and less commonly show isolated 5q deletion than do 5 years, but we did not exclude commonly referenced and
those in western populations.10 highly regarded older publications. We also searched the
The cause of myelodysplastic syndromes is known in reference lists of articles identified by this search strategy and
only 15% of cases (panel). Inherited predisposition to the selected those that we judged relevant. Several review articles
disorder is evident in a third of paediatric cases, including were included because they provide comprehensive
in children with Down’s syndrome, Fanconi’s anaemia, overviews that are beyond the scope of this Seminar. The
and neurofibromatosis. In adults, inherited predisposition reference list was modified during the peer-review process on
is less common but should be investigated in young adults the basis of comments from reviewers.
or in families with other cases of myelodysplastic

www.thelancet.com Vol 383 June 28, 2014 2239

 Seminar

Myelodysplastic syndromes with complex karyotypes

Panel: Causes of myelodysplastic syndromes tend to have larger 5q deletions than in the 5q syndrome;35
Antineoplastic agents this more aggressive phenotype could involve
Alkylating agents haploinsufficient tumour suppressor genes from the
• Busulfan neighbouring regions, including CTTNA136 or EGR1.37
• Carboplatin The selective clonal suppression of del(5q) cells by
• Carmustine lenalidomide seems to preserve del(5q) haemopoietic
• Chlorambucil stem cells29 and to be independent of the pathways
• Cisplatin mentioned above.38 A similar haploinsufficiency model
• Cyclophosphamide might also apply for other recurrent interstitial deletions
• Dacarbazine in myelodysplastic syndromes, including del(7q)39 and
• Lomustine del(20q).40,41
• Melphalan
Somatic gene mutations
Topoisomerase II inhibitors
High-throughput genomic methods have enabled the
• Daunorubicin
characterisation of many recurrently mutated genes in
• Doxorubicin
myelodysplastic syndromes (table 1), coding for
• Etoposide
transcription factors (TP53 or ETV6), but mostly for
• Mitoxantrone
epigenetic regulators involved in the methylation
• Razoxane
(DNMT3A) or hydroxymethylation (TET2, IDH1,
Purine analogues IDH2) of cytosines, or in covalent modifications of
• Fludarabine and others histones (EZH2, UTX, ASXL1). Mutations in those
Radiotherapy genes can be dominant-negative (DNMT3A), gain of
Environmental factors function (IDH1, IDH2), or loss of function (TET2,
• Tobacco ASXL1). They seem to result in global changes in gene
• Ionising radiation expression patterns and can also affect genomic
• Benzene exposure (and industrial hydrocarbons) stability.42 Since these mutations also probably arise in
• Agricultural compounds (pesticides, herbicides, fertilisers) haemopoietic stem cells43 and can be found in other
myeloid neoplasms, they are thought to affect clonal
dominance and progression of myelodysplastic
sideroblasts,24 and by external cues, including death syndromes1,44 rather than to determine the specific
signals (tumour necrosis factor,25 Fas26), or myelo- phenotype.45,46
suppressive cytokines (eg, transforming growth Recurrent mutations in genes encoding components of
factor β27). Intrinsic apoptotic signals seem to reflect the the splicing machinery, including SF3B1, SRSF2, U2AF1,
role of clonal chromosomal changes, gene mutations, and ZRSR2, have also been reported in myelodysplastic
or epigenetic changes, and extrinsic signals are related syndromes.47,48 They alter gene splicing, with many
to immune and microenvironmental insults. potential functional outcomes.48,49 Some of these
spliceosomal components are also involved in the
5q syndrome maintenance of genomic stability.50 By contrast with
Of the subtypes of myelodysplastic syndrome, mutations in epigenetic regulators, spliceosome
5q syndrome has the best understood pathogenesis. The mutations are highly characteristic of myelodysplastic
interstitial deletion del(5)(q31q33) originates in syndromes (and myelodysplastic syndrome with
haemopoietic stem cells28,29 and leads to myeloproliferative feature neoplasms) among myeloid
haploinsufficiency (ie, loss of one allele resulting in malignancies. SF3B1 mutations are closely associated
reduced gene expression, without gene mutation) of a with ring sideroblastic subtypes of myelodysplastic
variable number of genes, according to the extent of the syndromes;47 they could contribute directly to abnormal
deleted region. The shortest deleted segment identified iron retention in the mitochondria of erythroid
so far to result in the 5q phenotype encompasses about precursors, and thus formation of ringed sideroblasts.24,49
40 genes included in a common deleted region.30
Haploinsufficency for the ribosomal subunit RPS14 Epigenetic changes
induces a P53-dependent block in erythroid proliferation Epigenetic changes are particularly seen during
and differentiation,31,32 whereas haploinsufficiency of progression of myelodysplastic syndromes; they include
two micro-RNAs, mir-145 and mir-146a, leads to aberrant gene promoter methylation—eg, in the tumour
dysmegakaryopoiesis and thrombocytosis.33 Subclonal suppressor gene P15 INK4B.51 Aberrant methylation
mutations in the gene TP53, possibly promoted by the also arises in haemopoietic stem cells,3,4 but its relation
constant activation of P53, could contribute to to gene mutations in epigenetic regulators is unclear.52
progression to higher-risk disease.34 The prognostic contribution of aberrant methylation

2240 www.thelancet.com Vol 383 June 28, 2014

 Seminar

Immune attack Environmental exposure Ageing Radiotherapy and chemotherapy

(Micro-) environmental changes Somatic gene mutations Epigenetic changes Combined haploinsufficiency
(Osteoblast dysfunction?), (Epigenetic regulators, spliceosome (Promoter methylation) (Interstitial deletion)
immune deregulation genes)

Clonal expansion Increased progenitor apoptosis,

differentiation defect

HSC MDS-initiating MDS progenitors Cytopenias

? cells

Mesenchymal cells

AML
Risk of progression to AML
Clonal selection
(±additional genetic lesions)

Figure: Pathogenesis of myelodysplastic syndromes

Age-induced genetic, epigenetic, and immune-mediated changes in haemopoietic stem cells (HSC) lead to oligoclonal expansion of myelodysplastic stem cells, with
defective differentiation, characterised by increased apoptosis of erythroid and myeloid progenitors. Microenvironmental changes and immune deregulation
contribute to this differentiation defect. MDS=myelodysplastic syndromes. AML=acute myeloid leukaemia.

profiles, and their potential use as biomarkers in

Frequency of Gene function Prognosis
patients treated with hypomethylating agents, also mutations (%)
remain unclear.2
SF3B1 15–30% Spliceosome Favourable?
TET2 15–25% DNA hydroxymethylation Neutral
Microenvironment and immune cells
ASXL1 10–20% Histone modifications Unfavourable
Xenotransplantation assays and in-vitro experiments 25,53
RUNX1 5–15% Transcription factor Unfavourable
have shown the crucial role of microenvironmental
TP53 5–10% Transcription factor Unfavourable
cues in the maintenance and clinical expression of
DNMT3A 5–10% DNA methylation Unfavourable?
myelodysplastic syndromes.54 The haemopoietic stem-
NRAS, KRAS 5–10% Signal transduction Unfavourable (low-risk syndromes)
cell niche could contribute to the pathogenesis of these
disorders.55,56 Immune deregulation is shown by the SRSF2 5–10% Spliceosome Unfavourable

finding of clonal T-cell expansions in some patients, U2AF1 5–10% Spliceosome Unfavourable (low-risk syndromes)
especially those with hypoplastic syndromes. Expansion BCOR-L1 5–6% Transcription repressor Unfavourable
of distinct T-cell subpopulations could occur at different ZRSR2 5% Spliceosome Neutral?
disease stages; inflammatory Th17 cells could contribute EZH2 3–7% Histone modifications Unfavourable
to ineffective haemopoiesis in lower-risk myelo- ETV6 3% Transcription factor Unfavourable
dysplastic syndromes57 and regulatory T cells contribute JAK2 3–4% Signal transduction Favourable?
to evasion from antitumoral immunity in higher-risk
disease.58 Patients with higher-risk myelodysplastic IDH1, IDH2 4–5% DNA hydroxymethylation Unfavourable
and histone modifications
syndromes also have higher than normal numbers of
UTX 1–2% Histone modifications Unfavourable?
T regulatory cells,58 which suggests that progression is
facilitated by immune suppression. The mode of action Table 1: Recurrent somatic gene mutations in myelodysplastic syndromes
of several drugs in myelodysplastic syndromes,
including the immunomodulatory agent lenalidomide microenvironmental and immune modifications59
and hypomethylating agents, which cannot eradicate beyond their specific action on the myelodysplastic
myelodysplastic stem cells,3,29 could involve syndrome clone.60

www.thelancet.com Vol 383 June 28, 2014 2241

 Seminar
Diagnosis
Clinical findings
Clinical features are non-specific and mainly result from
cytopenias, especially anaemia, which is symptomatic in
many patients, leading to fatigue, poor quality of life, and
destabilisation of underlying cardiovascular disease.
Thrombocytopenia is commonly associated with platelet
dysfunction, potentially leading to bleeding symptoms
even in moderate thrombocytopenia. Similarly, infections
(especially with gram-negative bacilli, gram-positive cocci,
and fungi) can occur with only moderate neutropenia due
to frequent neutrophil function defects.61
Many patients with myelodysplastic syndromes also
have immune disorders, including relapsing poly-
chondritis, vasculitis, and seronegative polyarthritis.62,63
The two disorders tend to be diagnosed almost simul-
taneously, which suggests a pathophysiological relation.
Blood and marrow examination
90% of patients have anaemia that is typically, but not
always, macrocytic and non-regenerative. Neutropenia
and thrombocytopenia are seen at diagnosis in about a
third of patients, and rarely without anaemia. Small
numbers of circulating blasts can be found, rarely
exceeding 5%. However, on the peripheral blood smear,
200 cells should be counted to ensure correct
classification that depends partly on the number of
peripheral blasts (>1% or not). Leucocytosis and
immature granulocytes are rare on the differential count
except in chronic myelomonocytic leukaemia, now
classified among myelodysplastic–myeloproliferative
neoplasms and defined by blood monocytosis of more
than 1 × 10⁹ cells per L.6
Analysis of bone marrow is central to the diagnosis of
myelodysplastic syndromes. The bone marrow is
generally hypercellular and shows dysplastic features in
one or several myeloid series, generally differing from
those seen in deficiency of vitamin B12 or folate.6 The
marrow blast percentage (including agranular blasts and
myeloblasts, but not promyelocytes) should be assessed
on at least 500 nucleated cells. Ring sideroblasts
(erythroblasts with abnormal localisation of iron in
Proportion Karyotype Median
of patients survival
(%) (years)
Very good 4% –Y, del(11q) 5·4
Good 72% Normal, del(5q), del(12p), del(20q), double 4·8
including del(5q)
Intermediate 13% del(7q), +8, +19, i(17q), any other single or 2·7
double independent clones
Poor 4% −7, inv(3)/t(3q)/del(3q), double including 1·5
−7/del(7q); complex: 3 abnormalities
Very poor 7% Complex >3 abnormalities 0·7
AML=acute myeloid leukaemia. NR=not reached.
Table 2: Cytogenetic findings in patients with myelodysplastic syndromes, by their prognostic value8,68
2242
mitochondria around the nucleus) are counted after
staining with Prussian blue.
Generally, marrow aspirates are sufficient. The more
invasive trephine biopsy is, however, important to assess
marrow fibrosis, present in 15% of cases, and is useful
when the marrow is hypocellular, to differentiate
myelodysplastic syndromes from aplastic anaemia or
acute myeloid leukaemia.64 It can also enable detection, in
the absence of excess blasts, of the abnormal localisation
of immature precursors, which is associated with worse
prognosis.65 In most patients, aspirates are sufficient for
follow-up including for assessment of treatment efficacy.
Differential diagnosis
Diagnosis of myelodysplastic syndromes is generally
made readily on blood and marrow examination. All
other causes of cytopenias must be carefully excluded;
the list includes, but is not limited to, vitamin deficiencies
(ruled out by serum testing), autoimmune disease, liver
disease, hypersplenism, drug intake, exposure to
environmental toxins, aplastic anaemia, paroxysmal
nocturnal haemoglobinuria, bone-marrow infiltration by
malignancy, viral infections, and rare forms of hereditary
anaemias (such as congenital dyserythropoetic
anaemias). Diagnosis can be difficult when cytopenias
are moderate and marrow dysplasia is mild. In such
patients, detection of a chromosomal abnormality (and
possibly of a somatic mutation or abnormal flow
cytometry features)1,44,66 in marrow cells can point to a
clonal disorder, and therefore in the context to an early
myelodysplastic syndrome. In the absence of such
abnormalities, the diagnosis must be idiopathic cytopenia
of undetermined significance.67
Cytogenetic findings
An abnormal karyotype is shown by conventional
cytogenetic analysis in 40–50% of cases at diagnosis.68,69 By
contrast with acute myeloid leukaemia, in which balanced
translocations are frequent, myelodysplastic syndromes
are characterised by partial or complete loss or gain of
chromosomes, the most frequent findings being
deleted 5q, −7 or deleted 7q, +8, deleted 20q, and
deleted 17p; complex cytogenetic findings are common in
Time to 25% patients with a major excess of marrow blasts or with
AML evolution therapy-related myelodysplastic syndromes (table 2).
(years) Fluorescence in-situ analysis with specific probes
NR (especially for chromosomes 5, 7, 8, 17, and 20) can be
9·4 useful when fewer than 20 mitoses have been obtained for
conventional analysis or when the karyotype is complex,
2·5 to identify the chromosomes involved more accurately.
Cytogenetic analysis has major prognostic value for
1·7
myelodysplastic syndromes but can also enable diagnosis
0·7
in difficult cases. Such cases include patients with
unexplained isolated thrombocytopenia (deleted 20q),
elderly women with mild anaemia (deleted 5q), and
younger patients with moderate cytopenias (−7 or +8),70
confirming the clonal nature of the disease.
www.thelancet.com Vol 383 June 28, 2014
 Seminar

Other diagnostic tests
Other tests can be useful for diagnosis, in rare cases of
undefined cytopenias. The presence of a somatic mutation
other than TET2 mutation, reported in some healthy
individuals,71 can allow a diagnosis of a myelodysplastic
syndrome. Flow cytometry takes advantage of the frequent
abnormal expression of markers on marrow myeloid cells
in these syndromes. Consensus workshops have
established combinations of markers for which
abnormalities strongly suggest myelodysplastic
syndromes, but experience is needed for this approach.66
Patients whose diagnosis remains uncertain after
marrow examination and cytogenetic analysis generally
have moderate cytopenias and slowly evolving disease.
No therapeutic intervention at this stage has shown any
efficacy; if a very early diagnosis of myelodysplastic
syndromes is missed, the consequences are unlikely to
be severe except in younger patients.
Classification
Morphological classification of myelodysplastic syndromes
is based on the WHO 2008 criteria6 (table 3). The best
defined categories are refractory anaemia with excess
blasts (type 1 or 2 based on the marrow blast count being
below or above 10%), refractory anaemia with or without
ringed sideroblasts, refractory cytopenias with multilineage
dysplasia, and myelodysplastic syndromes with isolated
deleted 5q. Categories of refractory cytopenia with
unilineage dysplasia other than refractory anaemia have
proved less reproducible in clinical practice.72 Therapy-
related myelodysplastic syndromes are classified
separately, in a group that also includes therapy-related
acute myeloid leukaemia.
Boundaries include the myelodysplastic–myelo-
proliferative neoplasms group, in which at least 50% of
patients have chronic myelomonocytic leukaemias.
However, except for some cases of chronic myelomonocytic
leukemia, these disorders have generally limited pro-
liferative features and evolve mostly like typical
myelodysplastic syndromes.6 Patients who have refractory
anaemia with ringed sideroblasts and thrombocytosis,
also in this group, generally carry SF3B1 mutations (as do
those with refractory anaemia with ringed sideroblasts
alone); the disease is also mainly characterised by

Blood findings Bone-marrow findings

Myelodysplastic syndrome
Refractory cytopenia with unilineage dysplasia
(refractory anaemia; refractory neutropenia;
refractory thrombocytopenia)
Refractory anaemia with ring sideroblasts
Refractory cytopenia with multilineage dysplasia
Refractory anaemia with excess blasts 1
Refractory anaemia with excess blasts 2
Myelodysplastic syndrome unclassified
MDS associated with isolated del(5q)
Myelodysplastic–myeloproliferative neoplasms
Chronic myelomonocytic leukaemia 1
Chronic myelomonocytic leukaemia 2
Myelodysplastic or myeloproliferative disease,
unclassifiable
Provisional entity: refractory anaemia with ring
sideroblasts and thrombocytosis
Therapy-related neoplasm
Acute myeloid leukaemia or myelodysplastic
syndrome in individuals exposed to cytotoxic agents
One or two cytopenias; no or rare blasts (<1%)
Anaemia; no blasts
Cytopenia(s); no or rare blasts (<1%); no auer rods;
<1 × 10⁹ cells per L monocytes
Cytopenia(s); <5% blasts; no auer rods; <1 × 10⁹/L monocytes Dysplasia in one or several lineages; 5–9% blasts; no auer rods
Cytopenia(s); 5–19% blasts; with or without auer rods;
<1 × 10⁹/L monocytes
Cytopenias; <1% blasts
Anaemia; normal or increased platelet count in most cases;
no or rare blasts (<1%)
Persistent peripheral blood monocytosis (>1 × 10⁹/L);
no Philadelphia chromosome or BCR-ABL1 fusion gene;
<5% blasts
Persistent peripheral blood monocytosis (>1 × 10⁹/L);
no Philadelphia chromosome or BCR-ABL1 fusion gene;
<19% blasts
Morphological features of myelodysplastic syndrome;
prominent myeloproliferative features (platelets >600× 10⁹
cells per L, leucocytes >13 × 10⁹/L, splenomegaly);
no Philadelphia chromosome or BCR-ABL1 fusion gene;
no del(5q), t(3;3)(q21;q26), inv3(q21;q26); no underlying
myeloproliferative disease
Similar to refractory anaemia with ring sideroblasts; platelet
>600×10⁹ cells per L
··
One lineage dysplasia ≥10% of cells in one myeloid lineage; <5% blasts;
<15% of erythroid precursors ring sideroblasts
≥15% of erythroid precursors ring sideroblasts; erythroid dysplasia only;
<5% blasts
Dysplasia in ≥10% of cells in at least two myeloid lineages (neutrophil,
erythroid precursors, or megakaryocytes); <5% blasts in marrow; no auer
rods; with or without 15% ring sideroblasts
Dysplasia in one or several lineages ; 10–19% blasts; with or without auer
rods
Unequivocal dysplasia in <10% of cells in one or more myeloid lineages
accompanied by a cytogenetic abnormality is presumptive evidence for
diagnosis; <5% blasts
Normal to increased megakaryocytes with hypolobated nuclei; <5% blasts;
isolated del(5q) cytogenetic abnormality; no auer rods
Dysplasia in one or more cell lines; <10% blasts
Dysplasia in one or more cell lines; 10–19% blasts
··
Similar to refractory anaemia with ring sideroblasts; without del(5q)
··

Table 3: WHO 2008 classification6

www.thelancet.com Vol 383 June 28, 2014 2243

 Seminar

Bone-marrow blasts (%)
Number of cytopenias*
Cytogenetics
*Platelet count <100 × 10⁹/L; haemoglobin <100 g/L; absolute neutrophil count <1·8 × 10⁹/L.
Table 4: The international pronostic scoring sytem (IPSS)7 score values
anaemia.6,73 The 30% marrow blast threshold (subsequently
lowered to 20%) to distinguish myelodysplastic syndromes
from acute myeloid leukaemia should be critically
interpreted in regards to treatment, because acute myeloid
leukaemia is generally considered for chemotherapy and
higher-risk myelodysplastic syndromes for hypo-
methylating agents. For example, a younger patient with
15% marrow blasts and normal karyotype—judged to
have a myelodysplastic syndrome—would probably
benefit from chemotherapy, whereas an elderly patient
with 25% marrow blasts and complex karyotype—judged
to have acute myeloid leukaemia— might benefit more
from hypomethylating agents.
Prognostic factors
International prognostic scoring system (IPSS) and its
update
Many prognostic factors have been identified in
myelodysplastic syndromes but international efforts have
concentrated on identification of a small number of
features with independent prognostic value, routinely
available in all centres, which can be grouped in scoring
systems. A high percentage of marrow blasts, increasing
number and importance of cytopenias, and abnormal
karyotype are the most important independent factors of
poor prognosis in myelodysplastic syndromes; the IPSS7
allows classification of patients in four subgroups with
largely differing risks of progression to acute myeloid
leukaemia and survival (table 4, table 5).
Several attempts have been made to refine IPSS, still
used for drug approval by most health authorities,
especially in lower-risk myelodysplastic syndromes in
which it cannot distinguish between patients with longer
survival and those with only intermediate outcome.74,75
These refined systems include the WHO-based
0 points 0·5 points 1·0 point 1·5 points
<5% 5–10% ·· 11–20%
0–1 2–3 ·· ··
Good: Intermediate: Poor: complex ··
normal, Y, other ≥3 abnormalities,
del(5q), abnormalities chromosome 7
del(20q) abnormalities
prognostic scoring system (WPSS), which takes into
account WHO classification and requirements for
transfusion of red blood cells.74 The most important is
the revised IPSS (table 6),8 which also uses cytogenetic
abnormalities, cytopenias, and blast count for scoring
but with new thresholds. With the revised IPSS, 27% of
lower-risk myelodysplastic syndromes according to the
original IPSS are reclassified as having a higher risk
(table 7), and patients potentially need more intensive
treatment, whereas 18% of high-risk patients defined by
the original IPSS are reclassified as low risk.8
Other prognostic factors
Age is an important indicator of poor prognosis; however,
it is not included in the original or revised IPSS because it
could allow underestimation of the severity of
myelodysplastic syndromes in young patients. Indeed, the
loss of years of life expectancy is greater in younger than
for older adults with these disorders.76 However, age-
related factors, especially non-haematological comorbidity,
also clearly affects survival and must be taken into account
in decisions on intensive treatments. In a large study of
600 patients, the assessment of comorbidities by the Adult
Comorbidity Evaluation-27 showed that patients with
severe comorbidity had 50% lower survival than did those
without comorbidity, independently of age and IPSS risk
group.77 Similarly, the haemopoietic-stem-cell trans-
plantation-specific comorbidity index and the Charlson
comorbidity index are independent prognostic factors in
patients with lower-risk myelodysplastic syndromes,78
which suggests that these factors should be taken into
account in treatment decisions.
Bone-marrow fibrosis (grade ≥2) is independently
associated with poorer survival, in both lower-risk and
higher-risk myelodysplastic syndromes, so systematic
bone-marrow biopsy is justified at least at diagnosis.64
Somatic mutations have a strong effect on survival. The
2·0 points
presence of any of the mutations TP53, RUNX1, TP53,
21–30% EZH2, or ETV6 worsens prognosis,1,44 independently of
·· IPSS. ASXL1 and SRSF2 mutations also seem to be
·· associated with a poor prognosis.79,80
Flow cytometry features of marrow cells have
prognostic value with experienced researchers, but this
test cannot yet be generalised.81 High serum
concentrations of ferritin and lactate dehydrogenase are
also associated with poorer survival.82,83

Predictive factors for response to treatment

Low Intermediate 1 Intermediate 2 High Most prognostic factors in myelodysplastic syndromes
have been assessed in patients receiving supportive
Risk score 0 0·5–1·0 1·5–2·0 ≥2·5
care only. Because more effective treatments are
Proportion of patients (%) 33% 38% 22% 7%
emerging, prognosis is increasingly analysed in terms
Median survival (years) 5·7 3·5 1·2 0·4
of such treatments. For example, low baseline serum
Time to 25% AML evolution (years) 9·4 3·3 1·1 0·2
concentrations of erythropoietin can predict response
IPSS=international prognostic scoring system. AML=acute myeloid leukaemia. to erythropoiesis-stimulating drugs,84 whereas early
resistance to these drugs in lower-risk myelodysplastic
Table 5: IPSS prognostic risk category clinical outcomes
syndromes is associated with poorer outcome.85

2244 www.thelancet.com Vol 383 June 28, 2014

 Seminar

0 points 0·5 points 1·0 point 1·5 points 2·0 points 3·0 points 4·0 points
Cytogenetics* Very good ·· Good ·· Intermediate Poor Very poor
Bone-marrow blasts (%) ≤2% ·· >2 to <5% ·· 5–10% >10% ··
Haemoglobin (g/L) ≥100 ·· 80 to <100 <80 ·· ·· ··
Platelet count (×109/L) ≥100 50 to <100 <50 ·· ·· ·· ··
Absolute neutrophil count (×109/L) ≥0·8 <0·8 ·· ·· ·· ·· ··

*As in table 2.

Table 6: Revised international prognostic scoring system prognostic score values

Response to hypomethylating agents can be predicted

Very low Low Intermediate High Very high
by conventional factors (including performance status,
karyotype, erythrocyte transfusion requirements, Risk score ≤1·5 >1·5–3·0 >3·0–4·5 >4·5–6·0 >6·0
presence of circulating blasts),86 but possibly also Proportion of patients (%) 19% 38% 20% 13% 10%
somatic mutations; TP53 mutations predict poor Median survival (years) 8·8 5·3 3·0 1·6 0·8
response, whereas TET2, EZH2, or DNMT3A Time to 25% evolution to AML (years) NR 10·8 3·2 1·4 0·73
mutations, associated with neutral or unfavourable IPSS=international prognostic scoring system. AML=acute myeloid leukaemia. NR=not reached.
outcome in general, seem to be associated with
favourable response, although these findings remain Table 7: Revised IPSS prognostic risk category clinical outcomes
unconfirmed.87–90 Presence of deleted 5q is clearly
associated with erythroid response to lenalidomide; outcome.93 Various comorbidity scores can be used to
however, in patients with deleted 5q, a complex predict post-transplantation outcomes in patients with
karyotype, TP53 mutation, and a blast count above 5% myelodysplastic syndromes.93–95
predict poorer response to this drug.34,91 The optimum timing of allogeneic stem-cell
transplantation is a balance between a risk of transplant-
Treatment related mortality in patients who might expect long-term
Strategy survival without transplantation and a risk of relapse after
Treatment of myelodysplastic syndromes has improved transplantation in patients with advanced disease. In
lately but remains challenging. The therapeutic strategy higher-risk patients, both those younger than 60 years
remains largely based on the IPSS. In patients classified receiving myeloablative conditioning transplantation and
as high or intermediate 2 on the IPSS (higher risk) with older patients treated with non-myeloablative regimens,96–99
median survival if untreated of only about 12 months, early stem-cell transplantation was associated with a
treatment should aim to modify the disease course, survival advantage compared with other therapeutic
avoiding progression to acute myeloid leukaemia, and options.92 By contrast, early stem-cell transplantation had
extending survival. By contrast, in those classified as low an adverse effect on survival in lower-risk patients.92,100
or intermediate 1 on the IPSS (lower risk), survival is A high bone-marrow blast percentage before stem-cell
longer and many patients die from causes other than transplantation (especially if >10%) is associated with a
myelodysplastic syndromes. Therefore, their treatment higher risk of relapse, so the procedure is generally done
mainly aims to ameliorate the consequences of after a cytoreductive regimen (with chemotherapy or
cytopenias and transfusions and improve quality of life. perhaps hypomethylating agents) in patients with an
However, some lower-risk patients can benefit from excess of marrow blasts, although no evidence from
treatments generally applied to those at higher risk. prospective studies is available to support this approach.

Allogeneic stem-cell transplantation Chemotherapy

This approach remains, with few exceptions, the only
curative treatment of higher-risk myelodysplastic
syndromes, with prolonged disease-free survival of
35–50%.34,85 However, it can generally be offered only to a
few patients with myelodysplastic syndromes—younger
patients can be offered allogeneic stem-cell
transplantation for myeloablation and older patients (up
to 70 years or even older if they are very fit) can be offered
reduced-intensity stem-cell transplantation from an
HLA-identical donor.92
Many patients have comorbidities and impaired
functional status, which can lead to poor treatment
Intensive chemotherapy mainly uses combinations of
anthracyclines and cytarabine, as for acute myeloid
leukaemia,101–103 but it yields only 40–60% complete
remissions in patients with myelodysplastic syndromes
or those who progress to acute myeloid leukaemia and
shorter durations of complete remission (median
<12 months) than in de-novo acute myeloid
leukaemia.101–103 Patients with unfavourable karyotype
have fewer complete remissions and shorter durations of
remission.101 No drug combination (including fludarabine,
topotecan, and gemtuzumab ozogamicin, with cytarabine,
with or without granulocyte colony-stimulating factor

www.thelancet.com Vol 383 June 28, 2014 2245

 Seminar
[G-CSF]) has shown any survival advantage over classic
anthracycline–cytarabine combinations.102,104–106 Thus,
intensive chemotherapy has limited indication in higher-
risk myelodysplastic syndromes and is generally offered
to patients younger than 65 years with favourable
cytogenetics, especially as a bridge to allogeneic stem-cell
transplantation.
Low-dose cytarabine (20 mg/m² daily, 14–21 days every
month) yields complete remission and partial remission
rates of 15–20% in higher-risk myelodysplastic
syndromes, but no proven survival advantage.107,108
Response is seen only in patients without an unfavourable
karyotype.108,109 In a randomised study, low-dose cytarabine
was associated with significantly fewer responses, shorter
responses, and lower survival than was azacitidine,
irrespective of WHO classification and karyotype,
although it was more myelosuppressive.110
Hypomethylating agents
These drugs have become the first-line treatment in most
higher-risk myelodysplastic syndromes. After clinical
trials established clear efficacy of azacitidine in
myelodysplastic syndromes,111 a survival benefit with
azacitidine (75 mg/m² daily subcutaneously, 7 days every
4 weeks) was shown over conventional care regimens,
including best supportive care, low-dose cytarabine, or
intensive chemotherapy, in a randomised trial in
356 higher-risk patients,109 with median survival of
24·4 months versus 15 months. Progression to acute
myeloid leukaemia was delayed and independence from
erythrocyte transfusion was significantly more common.
The survival advantage with azacitidine was apparent
irrespective of age, marrow blast percentage, and
karyotype.109 Response to azacitidine was delayed in
many cases, with a median time to response of
2–3 months; some patients responded after only six
cycles.112 These findings suggest that patients should not
be classed as resistant before six cycles, unless they
clearly progress. Response was seen in 51% patients (17%
complete remission, 12% partial remission) and most
responses were only haematological improvement
(achievement of erythrocyte-transfusion dependence and
increase in platelet counts). Achievement of
haematological improvement, even in the absence of
complete or partial remission, was associated with better
survival.113 The median duration of response to azacitidine
was 13·6 months. The median number of cycles was 15
in responders, which suggests that long-term treatment
is necessary for survival improvement. The current
recommendation is to continue azacitidine until
progression or unacceptable toxicity, but optimum
duration of treatment in responders remains unknown.
Two phase 3 trials comparing decitabine (15 mg/m²
three times a day for 3 days every 6 weeks) with best
supportive care showed to have response rates similar
to those observed with azacitidine, but with no
significant survival advantage over best supportive
2246
care.114,115 This difference in survival benefit between
decitabine and azacitidine suggests intrinsic differences
between them, because the mechanisms of action are
not identical. It could also be the result of the low
number of cycles given (median three and four cycles,
in the two phase 3 trials), and possibly to a non-
optimum decitabine schedule. In an adjusted analysis
between azacitidine-treated and decitabine-treated
patients, no survival difference was reported for
patients younger than 65 years, but azacitidine showed
an advantage in older patients.115,116 A 5-day regimen of
decitabine (20 mg/m² daily intravenously) yielded a
39% complete remission rate and was superior to two
other regimens,117,118 but the effect of this regimen on
survival is unknown.
Since median survival is only 2 years with azacitidine
in high-risk myelodysplastic syndromes, combinations
of drugs with azacitidine are under investigation. Results
of some phase 2 trials combining azacitidine and valproic
acid,119 vorinostat,120 entinostat,121 lenalidomide,122
thalidomide,123 and gemtuzumab ozogamicin124 have
shown promising response rates, but no randomised
trial so far has shown any response or survival advantage
of these combinations over azacitidine alone.
Hypomethylating agents are increasingly being tested
before allogeneic stem-cell transplantation in patients
with excess blasts or an unfavourable karytotype, with
the aim to reduce the risk of relapse after transplantation,
and avoid the toxic effects of intensive chemotherapy. A
large retrospective analysis showed similar outcome fot
allogeneic stem-cell transplantation after treatment with
azacitidine and intensive chemotherapy, which needs to
be confirmed prospectively.125
Treatment of lower-risk myelodysplastic
syndromes
Treatment approaches mainly focus, at least initially, on
the treatment of cytopenias. Anaemia is the predominant
cytopenia in most patients with lower-risk myelodysplastic
syndromes. Chronic anaemia leads to increased
morbidity and lower quality of life,126,127 and many patients
need repeated erythrocyte transfusions, which might
(although this notion is disputed) result in potentially
deleterious iron overload in various organs.126
High-dose erythropoiesis-stimulating agents, including
recombinant erythropoietin or darbepoietin alfa, with or
without G-CSF, are generally the first-choice treatment
for anaemia in lower-risk myelodysplastic syndromes (at
least in the absence of deleted 5q) yielding 30–50%
erythroid responses of median duration 2 years. Response
rates are higher in patients with no or limited requirement
for erythrocyte transfusions and low serum erythropoietin
concentrations (below 200–500 IU/L) than in patients
without these characteristics.128 Both retrospective studies
and a prospective study show that erythropoiesis-
stimulating agents have no effect on progression to acute
myeloid leukaemia and that they could improve survival
www.thelancet.com Vol 383 June 28, 2014

in low-risk myelodysplastic syndromes compared with
erythrocyte transfusions alone.129–131
Erythropoiesis-stimulating agents are less effective in
lower-risk patients with deleted 5q than in those without
this feature.132 Lenalidomide yields erythrocyte
transfusion independence in two-thirds of such patients,
for a median duration of 2–3 years, and cytogenetic
responses in 50–70%; it has been approved, in the USA
and other countries, and in the European Union for
transfusion-dependent anaemia.133,134 TP53 mutations,
present in 20% of lower-risk patients with deleted 5q, are
associated with primary resistance to lenalidomide and a
high risk of progression to acute myeloid leukaemia;34
other therapeutic options might be better for these
patients. Because stem cells with deleted 5q can persist,
even in patients who achieve a complete cytogenetic
response to lenalidomide,29 long-term treatment could be
needed irrespective of some reports of sustained
responses after drug discontinuation.135 Two retrospective
analyses comparing the long-term outcome of lower-risk
patients with deleted 5q treated with and without
lenalidomide found no excess risk of acute myeloid
leukaemia with the drug.136,137
Treatment of anaemia after primary resistance to
erythropoiesis-stimulating agents (or lenalidomide in
patients with deleted 5q) or after relapse remains a
challenge. Antithymocyte globulins, with or without
ciclosporin, can yield an erythroid response, with
response to other cytopenias, especially thrombocytopenia
in 25–40% of patients, but in selected younger patients
with low-risk MDS,138–140 with limited erythrocyte
transfusion history, normal karyotype (or possibly
trisomy 8), no excess marrow blasts or HLA DR15
genotype, no deleted 5q, limited exposure to previous
treatments, and possibly hypocellular marrow, although
this finding is disputed.141
Hypomethylating agents are approved in the treatment
of lower-risk myelodysplastic syndromes in several
countries, can lead to transfusion independence in up to
40% of patients,111,142 and are effective against other
cytopenias. In a phase 2 trial of azacitidine alone or with
erythropoiesis-stimulating agents in patients with
erythrocyte-dependent lower-risk myelodysplastic
syndromes who showed resistance to erythropoiesis-
stimulating agents, transfusion independence was
achieved in only 17% of the patients, with no difference
between the two randomised groups.143
Lenalidomide enables transfusion independence in
25–30% of patients with lower-risk myelodysplastic
syndromes who do not have deleted 5q and who are
resistant to erythropoiesis-stimulating agents,144 but it is
not approved for this indication and should be used only
in clinical trials. Preliminary results suggest that the
combination of lenalidomide and erythropoiesis-
stimulating agents can lead to high rates of independence
from erythrocyte transfusion in patients resistant to an
erythropoiesis-stimulating agent alone.145
www.thelancet.com Vol 383 June 28, 2014
Seminar
Despite these treatments, many patients with lower-
risk myelodysplastic syndromes eventually need long-
term erythrocyte transfusions. The adverse effect of iron
overload remains disputed, as does the usefulness of
iron chelation in these patients. In particular, although
cardiac iron overload is a well-documented cause of
heart failure in children with thalassaemia,146 its
incidence and clinical consequences are less clear in
patients transfused for myelodysplastic syndromes,
especially when they have other causes of cardiac
morbidity. Clinically significant iron overload associated
with decreased cardiac function is, however, quite
common in patients who have received 100 or more red-
blood-cell concentrates.147
In the absence of prospective studies, retrospective
studies have suggested that adequate iron chelation can
improve survival in these patients;148–150 such studies can,
however, be subject to selection bias. Expert opinion151,152
suggests that chelation should be started in patients with
lower-risk myelodysplastic syndromes who have received
20–40 red-blood-cell concentrates, or if serum ferritin
concentration rises above 1500–2500 U/L. However, even
moderate iron overload is associated with increased
transplant-related mortality, so iron chelation therapy
should probably be offered early in patients who are
candidates for allogeneic stem-cell transplantation.153,154
Neutropenia and thrombocytopenia are less frequent
than is anaemia in lower-risk myelodysplastic syndromes,
and rarely occur alone or severely. Absolute neutrophil
counts are below 1·5 × 10⁹ cells per L in only 5–10% of
low-risk patients,75 and neutropenia is rarely associated
with life-threatening infection if no drugs that worsen
neutropenia are used. G-CSF and granulocyte-
macrophage colony-stimulating factor can improve
neutropenia in 60–75% of cases,155 but long-term use has
no proven effect on survival. Broad-spectrum antibiotics
should be used immediately in neutropenic patients with
myelodysplastic syndromes when fever or other signs of
infection occur.
Platelet counts below 50 × 10⁹ cells per L are seen in
30–35% of low-risk patients,75 and severe bleeding is rare
unless drugs that interfere with haemostasis are used.
High-dose androgens can improve thrombocytopenia in
about a third of affected patients, but response is
generally transient.156
The thrombopoietin-receptor agonist romiplostin in
high dose (500–1500 μg per week) yielded 55% platelet
responses in a phase 2 trial in lower-risk patients with
thrombocytopenia.157 However, a transient rise in marrow
blasts occurred in 15% of patients; this was reversible
after drug discontinuation. In a phase 3 placebo-
controlled study in patients with lower-risk
myelodysplastic syndromes and thrombocytopenia,
romiplostin transiently increased peripheral blasts in a
proportion of patients, although the rate of progression
to acute myeloid leukaemia did not differ significantly
between the study groups.158 Thrombopoietin-receptor
2247
 Seminar
agonists are not yet available for routine practice.
Antithymocyte globulins and hypomethylating agents
give platelet responses in 35–40% of patients with lower-
risk myelodysplastic syndromes, as well as erythroid
responses, and can be used in such patients.159,160
The classic IPSS,7 at diagnosis, can wrongly classify
some patients in lower-risk myelodysplastic syndromes,
because it does not incorporate marrow multilineage
dysplasia,74 erythrocyte transfusion dependence,7 severity
of thrombocytopenia,8 myelofibrosis, and somatic
mutations, which are associated with poorer prognosis.
The revised IPSS8 and specific scores designed for lower-
risk myelodysplastic syndromes address some of these
weaknesses.8,44,64,75 Patients classed as lower risk by the
IPSS who remain at lower risk, but have early resistance
to erythropoiesis-stimulating agents (patients with
non-deleted 5q)85 or resistance to lenalidomide (patients
with deleted 5q)134 also have poor survival.
Although prospective studies are scarce, hypo-
methylating agents are increasingly used in some of
these IPSS-defined lower-risk patients on the basis of
their effect on survival in higher-risk myelodysplastic
syndromes. Allogeneic stem-cell transplantation is also
sometimes proposed in patients younger than 60–70 years
in the absence of major response to hypomethylating
agents (or subsequent relapse).
Contributors
LA wrote the classification and treatment sections, RI wrote the biology
section, and PF wrote the incidence, diagnosis, and prognosis sections.
Declaration of interests
LA has received honoraria from Celgene, Novartis, Janssen, and Roche.
RI has received honoraria from Celgene. PF has received honoraria from
Celgene, Novartis, Janssen, and Roche.
References
1 Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point
mutations in myelodysplastic syndromes. N Engl J Med 2011;
364: 2496–506.
2 Shen L, Kantarjian H, Guo Y, et al. DNA methylation predicts
survival and response to therapy in patients with myelodysplastic
syndromes. J Clin Oncol 2010; 28: 605–13.
3 Will B, Zhou L, Vogler TO, et al. Stem and progenitor cells in
myelodysplastic syndromes show aberrant stage-specific expansion
and harbor genetic and epigenetic alterations. Blood 2012;
120: 2076–86.
4 Jiang Y, Dunbar A, Gondek LP, et al. Aberrant DNA methylation is
a dominant mechanism in MDS progression to AML. Blood 2009;
113: 1315–25.
5 Tefferi A, Vardiman JW. Myelodysplastic syndromes. N Engl J Med
2009; 361: 1872–85.
6 Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the
World Health Organization (WHO) classification of myeloid
neoplasms and acute leukemia: rationale and important changes.
Blood 2009; 114: 937–51.
7 Greenberg P, Cox C, LeBeau MM, et al. International scoring
system for evaluating prognosis in myelodysplastic syndromes.
Blood 1997; 89: 2079–88.
8 Greenberg PL, Tuechler H, Schanz J, et al. Revised international
prognostic scoring system for myelodysplastic syndromes. Blood
2012; 120: 2454–65.
9 Neukirchen J, Schoonen WM, Strupp C, et al. Incidence and
prevalence of myelodysplastic syndromes: data from the Düsseldorf
MDS-registry. Leuk Res 2011; 35: 1591–96.
10 Matsuda A, Germing U, Jinnai I, et al. Difference in clinical
features between Japanese and German patients with refractory
anemia in myelodysplastic syndromes. Blood 2005; 106: 2633–40.
2248
11 Pedersen-Bjergaard J, Daugaard G, Hansen SW, Philip P,
Larsen SO, Rørth M. Increased risk of myelodysplasia and
leukaemia after etoposide, cisplatin, and bleomycin for germ-cell
tumours. Lancet 1991; 338: 359–63.
12 McLaughlin P, Estey E, Glassman A, et al. Myelodysplasia and acute
myeloid leukemia following therapy for indolent lymphoma with
fludarabine, mitoxantrone, and dexamethasone (FND) plus
rituximab and interferon alpha. Blood 2005; 105: 4573–75.
13 Morrison VA, Rai KR, Peterson BL, et al. Therapy-related myeloid
leukemias are observed in patients with chronic lymphocytic
leukemia after treatment with fludarabine and chlorambucil: results
of an intergroup study, cancer and leukemia group B 9011.
J Clin Oncol 2002; 20: 3878–84.
14 Iwanaga M, Hsu WL, Soda M, et al. Risk of myelodysplastic
syndromes in people exposed to ionizing radiation: a retrospective
cohort study of Nagasaki atomic bomb survivors. J Clin Oncol 2011;
29: 428–34.
15 Cardis E, Vrijheid M, Blettner M, et al. Risk of cancer after low
doses of ionising radiation: retrospective cohort study in
15 countries. BMJ 2005; 331: 77.
16 Nisse C, Haguenoer JM, Grandbastien B, et al. Occupational and
environmental risk factors of the myelodysplastic syndromes in the
North of France. Br J Haematol 2001; 112: 927–35.
17 Aksoy M, Ozeriş S, Sabuncu H, Inanici Y, Yanardağ R. Exposure to
benzene in Turkey between 1983 and 1985: a haematological study
on 231 workers. Br J Ind Med 1987; 44: 785–87.
18 Rigolin GM, Cuneo A, Roberti MG, et al. Exposure to myelotoxic
agents and myelodysplasia: case-control study and correlation with
clinicobiological findings. Br J Haematol 1998; 103: 189–97.
19 Raza A, Gezer S, Mundle S, et al. Apoptosis in bone marrow biopsy
samples involving stromal and hematopoietic cells in 50 patients
with myelodysplastic syndromes. Blood 1995; 86: 268–76.
20 Raza A, Galili N. The genetic basis of phenotypic heterogeneity in
myelodysplastic syndromes. Nat Rev Cancer 2012; 12: 849–59.
21 Corey SJ, Minden MD, Barber DL, Kantarjian H, Wang JC,
Schimmer AD. Myelodysplastic syndromes: the complexity of
stem-cell diseases. Nat Rev Cancer 2007; 7: 118–29.
22 Walter MJ, Shen D, Ding L, et al. Clonal architecture of secondary
acute myeloid leukemia. N Engl J Med 2012; 366: 1090–98.
23 Parker JE, Mufti GJ, Rasool F, Mijovic A, Devereux S, Pagliuca A.
The role of apoptosis, proliferation, and the Bcl-2-related proteins in
the myelodysplastic syndromes and acute myeloid leukemia
secondary to MDS. Blood 2000; 96: 3932–38.
24 Tehranchi R, Invernizzi R, Grandien A, et al. Aberrant
mitochondrial iron distribution and maturation arrest characterize
early erythroid precursors in low-risk myelodysplastic syndromes.
Blood 2005; 106: 247–53.
25 Zang DY, Goodwin RG, Loken MR, Bryant E, Deeg HJ. Expression
of tumor necrosis factor-related apoptosis-inducing ligand, Apo2L,
and its receptors in myelodysplastic syndrome: effects on in vitro
hemopoiesis. Blood 2001; 98: 3058–65.
26 Claessens YE, Bouscary D, Dupont JM, et al. In vitro proliferation
and differentiation of erythroid progenitors from patients with
myelodysplastic syndromes: evidence for Fas-dependent apoptosis.
Blood 2002; 99: 1594–601.
27 Bhagat TD, Zhou L, Sokol L, et al. miR-21 mediates hematopoietic
suppression in MDS by activating TGF-β signaling. Blood 2013;
121: 2875–81.
28 Nilsson L, Astrand-Grundström I, Arvidsson I, et al. Isolation and
characterization of hematopoietic progenitor/stem cells in
5q-deleted myelodysplastic syndromes: evidence for involvement at
the hematopoietic stem cell level. Blood 2000; 96: 2012–21.
29 Tehranchi R, Woll PS, Anderson K, et al. Persistent malignant stem
cells in del(5q) myelodysplasia in remission. N Engl J Med 2010;
363: 1025–37.
30 Boultwood J, Fidler C, Strickson AJ, et al. Narrowing and genomic
annotation of the commonly deleted region of the 5q- syndrome.
Blood 2002; 99: 4638–41.
31 Ebert BL, Pretz J, Bosco J, et al. Identification of RPS14 as a
5q- syndrome gene by RNA interference screen. Nature 2008;
451: 335–39.
32 Barlow JL, Drynan LF, Hewett DR, et al. A p53-dependent
mechanism underlies macrocytic anemia in a mouse model of
human 5q- syndrome. Nat Med 2010; 16: 59–66.
www.thelancet.com Vol 383 June 28, 2014

33 Starczynowski DT, Kuchenbauer F, Argiropoulos B, et al.
Identification of miR-145 and miR-146a as mediators of the
5q- syndrome phenotype. Nat Med 2010; 16: 49–58.
34 Jädersten M, Saft L, Smith A, et al. TP53 mutations in low-risk
myelodysplastic syndromes with del(5q) predict disease
progression. J Clin Oncol 2011; 29: 1971–79.
35 Jerez A, Gondek LP, Jankowska AM, et al. Topography, clinical, and
genomic correlates of 5q myeloid malignancies revisited.
J Clin Oncol 2012; 30: 1343–49.
36 Liu TX, Becker MW, Jelinek J, et al. Chromosome 5q deletion and
epigenetic suppression of the gene encoding alpha-catenin
(CTNNA1) in myeloid cell transformation. Nat Med 2007; 13: 78–83.
37 Joslin JM, Fernald AA, Tennant TR, et al. Haploinsufficiency of
EGR1, a candidate gene in the del(5q), leads to the development of
myeloid disorders. Blood 2007; 110: 719–26.
38 Wei S, Chen X, Rocha K, et al. A critical role for phosphatase
haplodeficiency in the selective suppression of deletion 5q MDS by
lenalidomide. Proc Natl Acad Sci USA 2009; 106: 12974–79.
39 McNerney ME, Brown CD, Wang X, et al. CUX1 is a haploinsufficient
tumor suppressor gene on chromosome 7 frequently inactivated in
acute myeloid leukemia. Blood 2013; 121: 975–83.
40 Gurvich N, Perna F, Farina A, et al. L3MBTL1 polycomb protein,
a candidate tumor suppressor in del(20q12) myeloid disorders, is
essential for genome stability. Proc Natl Acad Sci USA 2010;
107: 22552–57.
41 Aziz A, Baxter EJ, Edwards C, et al. Cooperativity of imprinted
genes inactivated by acquired chromosome 20q deletions.
J Clin Invest 2013; 123: 2169–82.
42 Shih AH, Abdel-Wahab O, Patel JP, Levine RL. The role of
mutations in epigenetic regulators in myeloid malignancies.
Nat Rev Cancer 2012; 12: 599–612.
43 Damm F, Fontenay M, Bernard OA. Point mutations in
myelodysplastic syndromes. N Engl J Med 2011; 365: 1154–55, author
reply 155.
44 Bejar R, Stevenson KE, Caughey BA, et al. Validation of a prognostic
model and the impact of mutations in patients with lower-risk
myelodysplastic syndromes. J Clin Oncol 2012; 30: 3376–82.
45 Moran-Crusio K, Reavie L, Shih A, et al. Tet2 loss leads to increased
hematopoietic stem cell self-renewal and myeloid transformation.
Cancer Cell 2011; 20: 11–24.
46 Quivoron C, Couronné L, Della Valle V, et al. TET2 inactivation
results in pleiotropic hematopoietic abnormalities in mouse and is
a recurrent event during human lymphomagenesis. Cancer Cell
2011; 20: 25–38.
47 Papaemmanuil E, Cazzola M, Boultwood J, et al, and the Chronic
Myeloid Disorders Working Group of the International Cancer
Genome Consortium. Somatic SF3B1 mutation in myelodysplasia
with ring sideroblasts. N Engl J Med 2011; 365: 1384–95.
48 Yoshida K, Sanada M, Shiraishi Y, et al. Frequent pathway mutations
of splicing machinery in myelodysplasia. Nature 2011; 478: 64–69.
49 Visconte V, Rogers HJ, Singh J, et al. SF3B1 haploinsufficiency
leads to formation of ring sideroblasts in myelodysplastic
syndromes. Blood 2012; 120: 3173–86.
50 Xiao R, Sun Y, Ding JH, et al. Splicing regulator SC35 is essential
for genomic stability and cell proliferation during mammalian
organogenesis. Mol Cell Biol 2007; 27: 5393–402.
51 Khan H, Vale C, Bhagat T, Verma A. Role of DNA methylation in
the pathogenesis and treatment of myelodysplastic syndromes.
Semin Hematol 2013; 50: 16–37.
52 Pérez C, Martínez-Calle N, Martín-Subero JI, et al. TET2 mutations
are associated with specific 5-methylcytosine and
5-hydroxymethylcytosine profiles in patients with chronic
myelomonocytic leukemia. PLoS One 2012; 7: e31605.
53 Marcondes AM, Mhyre AJ, Stirewalt DL, Kim SH, Dinarello CA,
Deeg HJ. Dysregulation of IL-32 in myelodysplastic syndrome and
chronic myelomonocytic leukemia modulates apoptosis and
impairs NK function. Proc Natl Acad Sci USA 2008; 105: 2865–70.
54 Raaijmakers MH, Mukherjee S, Guo S, et al. Bone progenitor
dysfunction induces myelodysplasia and secondary leukaemia.
Nature 2010; 464: 852–57.
55 Blau O, Baldus CD, Hofmann WK, et al. Mesenchymal stromal cells
of myelodysplastic syndrome and acute myeloid leukemia patients
have distinct genetic abnormalities compared with leukemic blasts.
Blood 2011; 118: 5583–92.
www.thelancet.com Vol 383 June 28, 2014
Seminar
56 Muguruma Y, Matsushita H, Yahata T, et al. Establishment of a
xenograft model of human myelodysplastic syndromes.
Haematologica 2011; 96: 543–51.
57 Kordasti SY, Afzali B, Lim Z, et al. IL-17-producing CD4(+) T cells,
pro-inflammatory cytokines and apoptosis are increased in low risk
myelodysplastic syndrome. Br J Haematol 2009; 145: 64–72.
58 Kordasti SY, Ingram W, Hayden J, et al. CD4+CD25high Foxp3+
regulatory T cells in myelodysplastic syndrome (MDS). Blood 2007;
110: 847–50.
59 Costantini B, Kordasti S, Kulasekararaj AG, et al. The effects of
5-azacytidine on the function and number of regulatory T-cells and
T-effectors in myelodysplastic syndrome. Haematologica 2013;
98: 1196–205.
60 Tsai HC, Li H, Van Neste L, et al. Transient low doses of
DNA-demethylating agents exert durable antitumor effects on
hematological and epithelial tumor cells. Cancer Cell 2012;
21: 430–46.
61 Toma A, Fenaux P, Dreyfus F, Cordonnier C. Infections in
myelodysplastic syndromes. Haematologica 2012; 97: 1459–70.
62 Hebbar M, Kozlowski D, Wattel E, et al. Association between
myelodysplastic syndromes and inflammatory bowel diseases.
Report of seven new cases and review of the literature. Leukemia
1997; 11: 2188–91.
63 Hebbar M, Brouillard M, Wattel E, et al. Association of
myelodysplastic syndrome and relapsing polychondritis: further
evidence. Leukemia 1995; 9: 731–33.
64 Della Porta MG, Malcovati L, Boveri E, et al. Clinical relevance of
bone marrow fibrosis and CD34-positive cell clusters in primary
myelodysplastic syndromes. J Clin Oncol 2009; 27: 754–62.
65 Verburgh E, Achten R, Maes B, et al. Additional prognostic value of
bone marrow histology in patients subclassified according to the
International Prognostic Scoring System for myelodysplastic
syndromes. J Clin Oncol 2003; 21: 273–82.
66 Westers TM, Ireland R, Kern W, et al. Standardization of flow
cytometry in myelodysplastic syndromes: a report from an
international consortium and the European LeukemiaNet Working
Group. Leukemia 2012; 26: 1730–41.
67 Wimazal F, Fonatsch C, Thalhammer R, et al. Idiopathic cytopenia
of undetermined significance (ICUS) versus low risk MDS:
the diagnostic interface. Leuk Res 2007; 31: 1461–68.
68 Haase D, Germing U, Schanz J, et al. New insights into the
prognostic impact of the karyotype in MDS and correlation with
subtypes: evidence from a core dataset of 2124 patients. Blood 2007;
110: 4385–95.
69 Schanz J, Steidl C, Fonatsch C, et al. Coalesced multicentric
analysis of 2,351 patients with myelodysplastic syndromes indicates
an underestimation of poor-risk cytogenetics of myelodysplastic
syndromes in the international prognostic scoring system.
J Clin Oncol 2011; 29: 1963–70.
70 Braun T, de Botton S, Taksin AL, et al. Characteristics and outcome
of myelodysplastic syndromes (MDS) with isolated 20q deletion:
a report on 62 cases. Leuk Res 2011; 35: 863–67.
71 Busque L, Patel JP, Figueroa ME, et al. Recurrent somatic TET2
mutations in normal elderly individuals with clonal hematopoiesis.
Nat Genet 2012; 44: 1179–81.
72 Maassen A, Strupp C, Giagounidis A, et al. Validation and
proposals for a refinement of the WHO 2008 classification of
myelodysplastic syndromes without excess of blasts. Leuk Res
2013; 37: 64–70.
73 Malcovati L, Papaemmanuil E, Bowen DT, et al, for the Chronic
Myeloid Disorders Working Group of the International Cancer
Genome Consortium and of the Associazione Italiana per la Ricerca
sul Cancro Gruppo Italiano Malattie Mieloproliferative. Clinical
significance of SF3B1 mutations in myelodysplastic syndromes and
myelodysplastic/myeloproliferative neoplasms. Blood 2011;
118: 6239–46.
74 Malcovati L, Germing U, Kuendgen A, et al. Time-dependent
prognostic scoring system for predicting survival and leukemic
evolution in myelodysplastic syndromes. J Clin Oncol 2007;
25: 3503–10.
75 Garcia-Manero G, Shan J, Faderl S, et al. A prognostic score for
patients with lower risk myelodysplastic syndrome. Leukemia 2008;
22: 538–43.
2249
 Seminar
76 Morel P, Declercq C, Hebbar M, Bauters F, Fenaux P. Prognostic
factors in myelodysplastic syndromes: critical analysis of the impact
of age and gender and failure to identify a very-low-risk group using
standard mortality ratio techniques. Br J Haematol 1996; 94: 116–19.
77 Naqvi K, Garcia-Manero G, Sardesai S, et al. Association of
comorbidities with overall survival in myelodysplastic syndrome:
development of a prognostic model. J Clin Oncol 2011; 29: 2240–46.
78 Sperr WR, Wimazal F, Kundi M, et al. Comorbidity as prognostic
variable in MDS: comparative evaluation of the HCT-CI and CCI in
a core dataset of 419 patients of the Austrian MDS Study Group.
Ann Oncol 2010; 21: 114–19.
79 Thol F, Friesen I, Damm F, et al. Prognostic significance of ASXL1
mutations in patients with myelodysplastic syndromes. J Clin Oncol
2011; 29: 2499–506.
80 Thol F, Kade S, Schlarmann C, et al. Frequency and prognostic
impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with
myelodysplastic syndromes. Blood 2012; 119: 3578–84.
81 van de Loosdrecht AA, Westers TM, Westra AH, Dräger AM,
van der Velden VH, Ossenkoppele GJ. Identification of distinct
prognostic subgroups in low- and intermediate-1-risk myelodysplastic
syndromes by flow cytometry. Blood 2008; 111: 1067–77.
82 Germing U, Hildebrandt B, Pfeilstöcker M, et al. Refinement of the
international prognostic scoring system (IPSS) by including LDH
as an additional prognostic variable to improve risk assessment in
patients with primary myelodysplastic syndromes (MDS). Leukemia
2005; 19: 2223–31.
83 Malcovati L, Della Porta MG, Cazzola M. Predicting survival and
leukemic evolution in patients with myelodysplastic syndrome.
Haematologica 2006; 91: 1588–90.
84 Hellström-Lindberg E, Negrin R, Stein R, et al. Erythroid response
to treatment with G-CSF plus erythropoietin for the anaemia of
patients with myelodysplastic syndromes: proposal for a predictive
model. Br J Haematol 1997; 99: 344–51.
85 Kelaidi C, Park S, Sapena R, et al. Long-term outcome of anemic
lower-risk myelodysplastic syndromes without 5q deletion refractory
to or relapsing after erythropoiesis-stimulating agents. Leukemia
2013; 27: 1283–90.
86 Itzykson R, Thépot S, Quesnel B, et al, and the Groupe
Francophone des Myelodysplasies(GFM). Prognostic factors for
response and overall survival in 282 patients with higher-risk
myelodysplastic syndromes treated with azacitidine. Blood 2011;
117: 403–11.
87 Itzykson R, Kosmider O, Cluzeau T, et al, and the Groupe
Francophone des Myelodysplasies (GFM). Impact of TET2 mutations
on response rate to azacitidine in myelodysplastic syndromes and
low blast count acute myeloid leukemias. Leukemia 2011; 25: 1147–52.
88 Kulasekararaj AG, Mohamedali AM, Smith AE, et al. Polycomb
Complex Group Gene Mutations and Their Prognostic Relevance In
5-Azacitidine Treated Myelodysplastic Syndrome Patients.
ASH Annual Meeting Abstracts 2010; 116: 125-.
89 Kulasekararaj AG, Smith AE, Mian SA, et al. TP53 mutations in
myelodysplastic syndrome are strongly correlated with aberrations
of chromosome 5, and correlate with adverse prognosis.
Br J Haematol 2013; 160: 660–72.
90 Traina F, Jankowska AM, Visconte V, et al. Impact of Molecular
Mutations on Treatment Response to Hypomethylating Agents in
MDS. ASH Annual Meeting Abstracts 2011; 118: 461.
91 List A, Giagounidis A, Backstrom J, Fu T, Fenaux P. Early
lenalidomide (LEN) dose intensity and durable RBC-transfusion
independence (RBC-TI) in patients (pts) with low-/int-1-risk
myelodysplastic syndromes (MDS) and del5q. J Clin Oncol 2011;
29: 6522.
92 Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of
allogeneic bone marrow transplantation for the myelodysplastic
syndromes: delayed transplantation for low-risk myelodysplasia is
associated with improved outcome. Blood 2004; 104: 579–85.
93 Sorror ML, Sandmaier BM, Storer BE, et al. Comorbidity and
disease status based risk stratification of outcomes among patients
with acute myeloid leukemia or myelodysplasia receiving allogeneic
hematopoietic cell transplantation. J Clin Oncol 2007; 25: 4246–54.
94 Sperr WR, Wimazal F, Kundi M, et al. Survival analysis and AML
development in patients with de novo myelodysplastic syndromes:
comparison of six different prognostic scoring systems.
Ann Hematol 2001; 80: 272–77.
2250
95 Zipperer E, Pelz D, Nachtkamp K, et al. The hematopoietic stem
cell transplantation comorbidity index is of prognostic relevance for
patients with myelodysplastic syndrome. Haematologica 2009;
94: 729–32.
96 Anderson JE, Appelbaum FR, Schoch G, et al. Allogeneic marrow
transplantation for myelodysplastic syndrome with advanced
disease morphology: a phase II study of busulfan,
cyclophosphamide, and total-body irradiation and analysis of
prognostic factors. J Clin Oncol 1996; 14: 220–26.
97 Arnold R, de Witte T, van Biezen A, et al, for the European Blood
and Marrow Transplantation Group. Unrelated bone marrow
transplantation in patients with myelodysplastic syndromes and
secondary acute myeloid leukemia: an EBMT survey.
Bone Marrow Transplant 1998; 21: 1213–16.
98 Sierra J, Pérez WS, Rozman C, et al. Bone marrow transplantation
from HLA-identical siblings as treatment for myelodysplasia. Blood
2002; 100: 1997–2004.
99 Castro-Malaspina H, Harris RE, Gajewski J, et al. Unrelated donor
marrow transplantation for myelodysplastic syndromes: outcome
analysis in 510 transplants facilitated by the National Marrow Donor
Program. Blood 2002; 99: 1943–51.
100 Koreth J, Pidala J, Perez WS, et al. Role of reduced-intensity
conditioning allogeneic hematopoietic stem-cell transplantation in
older patients with de novo myelodysplastic syndromes: an
international collaborative decision analysis. J Clin Oncol 2013;
31: 2662–70.
101 Knipp S, Hildebrand B, Kündgen A, et al. Intensive chemotherapy
is not recommended for patients aged >60 years who have
myelodysplastic syndromes or acute myeloid leukemia with
high-risk karyotypes. Cancer 2007; 110: 345–52.
102 Kantarjian H, Beran M, Cortes J, et al. Long-term follow-up results
of the combination of topotecan and cytarabine and other intensive
chemotherapy regimens in myelodysplastic syndrome. Cancer 2006;
106: 1099–109.
103 Wattel E, Solary E, Leleu X, et al. A prospective study of
autologous bone marrow or peripheral blood stem cell
transplantation after intensive chemotherapy in myelodysplastic
syndromes. Groupe Français des Myélodysplasies. Group
Ouest-Est d’étude des Leucémies aiguës myéloïdes. Leukemia
1999; 13: 524–29.
104 Estey EH, Thall PF, Cortes JE, et al. Comparison of idarubicin +
ara-C-, fludarabine + ara-C-, and topotecan + ara-C-based regimens
in treatment of newly diagnosed acute myeloid leukemia, refractory
anemia with excess blasts in transformation, or refractory anemia
with excess blasts. Blood 2001; 98: 3575–83.
105 Sekeres MA, Maciejewski JP, Erba HP, et al. A Phase 2 study of
combination therapy with arsenic trioxide and gemtuzumab
ozogamicin in patients with myelodysplastic syndromes or
secondary acute myeloid leukemia. Cancer 2011; 117: 1253–61.
106 Estey EH, Thall PF, Giles FJ, et al. Gemtuzumab ozogamicin with
or without interleukin 11 in patients 65 years of age or older with
untreated acute myeloid leukemia and high-risk myelodysplastic
syndrome: comparison with idarubicin plus continuous-infusion,
high-dose cytosine arabinoside. Blood 2002; 99: 4343–49.
107 Cheson BD, Simon R. Low-dose ara-C in acute nonlymphocytic
leukemia and myelodysplastic syndromes: a review of 20 years’
experience. Semin Oncol 1987; 14 (suppl 1): 126–33.
108 Fenaux P, Lai JL, Gardin C, Bauters F. Cytogenetics are a predictive
factor of response to low dose Ara-C in acute myelogenous
leukemia (AML) in the elderly. Leukemia 1990; 4: 312.
109 Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al, for the
International Vidaza High-Risk MDS Survival Study Group.
Efficacy of azacitidine compared with that of conventional care
regimens in the treatment of higher-risk myelodysplastic
syndromes: a randomised, open-label, phase III study.
Lancet Oncol 2009; 10: 223–32.
110 Fenaux P, Gattermann N, Seymour JF, et al. Prolonged survival
with improved tolerability in higher-risk myelodysplastic
syndromes: azacitidine compared with low dose ara-C.
Br J Haematol 2010; 149: 244–49.
111 Silverman LR, Demakos EP, Peterson BL, et al. Randomized
controlled trial of azacitidine in patients with the myelodysplastic
syndrome: a study of the cancer and leukemia group B. J Clin Oncol
2002; 20: 2429–40.
www.thelancet.com Vol 383 June 28, 2014

112 Silverman LR, Fenaux P, Mufti GJ, et al. Continued azacitidine
therapy beyond time of first response improves quality of response
in patients with higher-risk myelodysplastic syndromes. Cancer
2011; 117: 2697–702.
113 Gore SD, Fenaux P, Santini V, et al. A multivariate analysis of the
relationship between response and survival among patients with
higher-risk myelodysplastic syndromes treated within azacitidine or
conventional care regimens in the randomized AZA-001 trial.
Haematologica 2013; 98: 1067–72.
114 Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves
patient outcomes in myelodysplastic syndromes: results of a
phase III randomized study. Cancer 2006; 106: 1794–803.
115 Lübbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best
supportive care in elderly patients with intermediate- or high-risk
myelodysplastic syndrome (MDS) ineligible for intensive
chemotherapy: final results of the randomized phase III study of
the European Organisation for Research and Treatment of Cancer
Leukemia Group and the German MDS Study Group. J Clin Oncol
2011; 29: 1987–96.
116 Lee YG, Kim I, Yoon SS, et al, for the Korean Society of
Haematology AML/MDS working party. Comparative analysis
between azacitidine and decitabine for the treatment of
myelodysplastic syndromes. Br J Haematol 2013; 161: 339–47.
117 Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a
randomized study of 3 schedules of low-dose decitabine in
higher-risk myelodysplastic syndrome and chronic myelomonocytic
leukemia. Blood 2007; 109: 52–57.
118 Steensma DP, Baer MR, Slack JL, et al. Multicenter study of
decitabine administered daily for 5 days every 4 weeks to adults with
myelodysplastic syndromes: the alternative dosing for outpatient
treatment (ADOPT) trial. J Clin Oncol 2009; 27: 3842–48.
119 Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al.
Phase 1/2 study of the combination of 5-aza-2´-deoxycytidine with
valproic acid in patients with leukemia. Blood 2006; 108: 3271–79.
120 Silverman L, Verma A, Odchimar-Reissig R, et al. A phase I/II study of
vorinostat, an oral histone deacetylase inhibitor, in combination with
azacitidine in patients with the myelodysplastic syndrome (MDS) and
acute myeloid leukemia (AML). Initial results of the phase I trial: A
New York Cancer Consortium. J Clin Oncol 2008; 26: abstr 7000.
121 Prebet T, Gore SD, Sun Z, et al. Prolonged Administration of
Azacitidine with or without Entinostat Increases Rate of
Hematologic Normalization for Myelodysplastic Syndrome and
Acute Myeloid Leukemia with Myelodysplasia-Related Changes:
Results of the US Leukemia Intergroup Trial E1905.
ASH Annual Meeting Abstracts 2010; 116: 601.
122 Sekeres MA, Tiu RV, Komrokji R, et al. Phase 2 study of the
lenalidomide and azacitidine combination in patients with
higher-risk myelodysplastic syndromes. Blood 2012; 120: 4945–51.
123 Raza A, Mehdi M, Mumtaz M, Ali F, Lascher S, Galili N.
Combination of 5-azacytidine and thalidomide for the treatment of
myelodysplastic syndromes and acute myeloid leukemia. Cancer
2008; 113: 1596–604.
124 Nand S, Godwin J, Smith S, et al. Hydroxyurea, azacitidine and
gemtuzumab ozogamicin therapy in patients with previously
untreated non-M3 acute myeloid leukemia and high-risk
myelodysplastic syndromes in the elderly: results from a pilot trial.
Leuk Lymphoma 2008; 49: 2141–47.
125 Platzbecker U, Wermke M, Radke J, et al. Azacitidine for treatment
of imminent relapse in MDS or AML patients after allogeneic
HSCT: results of the RELAZA trial. Leukemia 2012; 26: 381–89.
126 Fenaux P, Rose C. Impact of iron overload in myelodysplastic
syndromes. Blood Rev 2009; 23 (suppl 1): S15–19.
127 Crawford J, Cella D, Cleeland CS, et al. Relationship between
changes in hemoglobin level and quality of life during
chemotherapy in anemic cancer patients receiving epoetin alfa
therapy. Cancer 2002; 95: 888–95.
128 Hellström-Lindberg E, Gulbrandsen N, Lindberg G, et al, and the
Scandinavian MDS Group. A validated decision model for treating
the anaemia of myelodysplastic syndromes with erythropoietin +
granulocyte colony-stimulating factor: significant effects on quality
of life. Br J Haematol 2003; 120: 1037–46.
129 Park S, Grabar S, Kelaidi C, et al, for the GFM group (Groupe
Francophone des Myélodysplasies). Predictive factors of response and
survival in myelodysplastic syndrome treated with erythropoietin and
G-CSF: the GFM experience. Blood 2008; 111: 574–82.
www.thelancet.com Vol 383 June 28, 2014
Seminar
130 Jädersten M, Malcovati L, Dybedal I, et al. Erythropoietin and
granulocyte-colony stimulating factor treatment associated with
improved survival in myelodysplastic syndrome. J Clin Oncol 2008;
26: 3607–13.
131 Greenberg PL, Sun Z, Miller KB, et al. Treatment of myelodysplastic
syndrome patients with erythropoietin with or without granulocyte
colony-stimulating factor: results of a prospective randomized
phase 3 trial by the Eastern Cooperative Oncology Group (E1996).
Blood 2009; 114: 2393–400.
132 Kelaidi C, Park S, Brechignac S, et al, and the Groupe
Francophone des Myélodysplasies (GFM). Treatment of
myelodysplastic syndromes with 5q deletion before the
lenalidomide era; the GFM experience with EPO and thalidomide.
Leuk Res 2008; 32: 1049–53.
133 List A, Dewald G, Bennett J, et al, for the Myelodysplastic
Syndrome-003 Study Investigators. Lenalidomide in the
myelodysplastic syndrome with chromosome 5q deletion.
N Engl J Med 2006; 355: 1456–65.
134 Fenaux P, Giagounidis A, Selleslag D, et al, for the MDS-004
Lenalidomide del5q Study Group. A randomized phase 3 study of
lenalidomide versus placebo in RBC transfusion-dependent patients
with low-/intermediate-1-risk myelodysplastic syndromes with
del5q. Blood 2011; 118: 3765–76.
135 Giagounidis AA, Kulasekararaj A, Germing U, et al. Long-term
transfusion independence in del(5q) MDS patients who discontinue
lenalidomide. Leukemia 2012; 26: 855–58.
136 Adès L, Le Bras F, Sebert M, et al. Treatment with lenalidomide
does not appear to increase the risk of progression in lower risk
myelodysplastic syndromes with 5q deletion. A comparative
analysis by the Groupe Francophone des Myelodysplasies.
Haematologica 2012; 97: 213–18.
137 Kuendgen A, Lauseker M, List AF, et al. Lenalidomide does not
increase AML progression risk in RBC transfusion-dependent
patients with Low- or Intermediate-1-risk MDS with del(5q):
a comparative analysis. Leukemia 2013; 27: 1072–79.
138 Passweg JR, Giagounidis AA, Simcock M, et al.
Immunosuppressive therapy for patients with myelodysplastic
syndrome: a prospective randomized multicenter phase III trial
comparing antithymocyte globulin plus cyclosporine with best
supportive care--SAKK 33/99. J Clin Oncol 2011; 29: 303–09.
139 Molldrem JJ, Caples M, Mavroudis D, Plante M, Young NS,
Barrett AJ. Antithymocyte globulin for patients with
myelodysplastic syndrome. Br J Haematol 1997; 99: 699–705.
140 Sloand EM, Wu CO, Greenberg P, Young N, Barrett J. Factors
affecting response and survival in patients with myelodysplasia
treated with immunosuppressive therapy. J Clin Oncol 2008;
26: 2505–11.
141 Saunthararajah Y, Nakamura R, Wesley R, Wang Q J, Barrett AJ.
A simple method to predict response to immunosuppressive
therapy in patients with myelodysplastic syndrome. Blood 2003;
102: 3025–27.
142 Silverman LR, McKenzie DR, Peterson BL, et al, for the Cancer and
Leukemia Group B. Further analysis of trials with azacitidine in
patients with myelodysplastic syndrome: studies 8421, 8921, and
9221 by the Cancer and Leukemia Group B. J Clin Oncol 2006;
24: 3895–903.
143 Boehrer S, Beyne-Rauzy O, Prebet T, et al. Interim results of a
randomized phase II trial of azacitidine (AZA) +/− epo in lower risk
myelodysplastic syndrome (MDS) resistant to an erythropoietic
stimulating agent (ESA) alone. Blood 2010; 116: 784.
144 Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide
in transfusion-dependent, low-risk, and intermediate-1 risk
myelodysplastic syndromes with karyotypes other than deletion 5q.
Blood 2008; 111: 86–93.
145 Komrokji RS, Lancet JE, Swern AS, et al. Combined treatment with
lenalidomide and epoetin alfa in lower-risk patients with
myelodysplastic syndrome. Blood 2012; 120: 3419–24.
146 Davis BA, O’Sullivan C, Jarritt PH, Porter JB. Value of sequential
monitoring of left ventricular ejection fraction in the management
of thalassemia major. Blood 2004; 104: 263–69.
147 Jensen PD, Jensen FT, Christensen T, Eiskjaer H, Baandrup U,
Nielsen JL. Evaluation of myocardial iron by magnetic resonance
imaging during iron chelation therapy with deferrioxamine:
indication of close relation between myocardial iron content and
chelatable iron pool. Blood 2003; 101: 4632–39.
2251
 Seminar
148 Rose C, Brechignac S, Vassilief D, et al, for the GFM (Groupe
Francophone des Myélodysplasies). Does iron chelation therapy
improve survival in regularly transfused lower risk MDS patients?
A multicenter study by the GFM (Groupe Francophone des
Myélodysplasies). Leuk Res 2010; 34: 864–70.
149 Leitch HA. Improving clinical outcome in patients with
myelodysplastic syndrome and iron overload using iron chelation
therapy. Leuk Res 2007; 31 (suppl 3): S7–9.
150 Neukirchen J, Fox F, Kündgen A, et al. Improved survival in MDS
patients receiving iron chelation therapy – a matched pair analysis
of 188 patients from the Düsseldorf MDS registry. Leuk Res 2012;
36: 1067–70.
151 Gattermann N, Porter J, Lopes L, Seymour J. Consensus statement
on iron overload in myelodysplastic syndromes.
Hematol Oncol Clin North Am 2005; 19 (suppl 1): 18–25.
152 Greenberg PL. Myelodysplastic syndromes: iron overload
consequences and current chelating therapies.
J Natl Compr Canc Netw 2006; 4: 91–96.
153 Alessandrino EP, Della Porta MG, Bacigalupo A, et al. Prognostic
impact of pre-transplantation transfusion history and secondary
iron overload in patients with myelodysplastic syndrome
undergoing allogeneic stem cell transplantation: a study from the
Gruppo Italiano Trapianto di Midollo Osseo (GITMO).
Haematologica 2010; 95: 476–84.
154 Armand P, Kim HT, Cutler CS, et al. Prognostic impact of elevated
pretransplantation serum ferritin in patients undergoing
myeloablative stem cell transplantation. Blood 2007; 109: 4586–88.
2252
155 Hellström-Lindberg E, Ahlgren T, Beguin Y, et al. Treatment of
anemia in myelodysplastic syndromes with granulocyte
colony-stimulating factor plus erythropoietin: results from a
randomized phase II study and long-term follow-up of 71 patients.
Blood 1998; 92: 68–75.
156 Wattel E, Preudhomme C, Hecquet B, et al. p53 mutations are
associated with resistance to chemotherapy and short survival in
hematologic malignancies. Blood 1994; 84: 3148–57.
157 Kantarjian H, Fenaux P, Sekeres MA, et al. Phase 1/2 study of AMG
531 in thrombocytopenic patients (pts) with low-risk
myelodysplastic syndrome (MDS): update including extended
treatment. ASH Annual Meeting Abstracts 2007; 110: 250.
158 Kantarjian HM, Mufti GJ, Fenaux P, et al. Treatment with the
thrombopoietin (TPO)-receptor agonist romiplostim in
thrombocytopenic patients (Pts) with low or intermediate-1 (int-1)
risk myelodysplastic syndrome (MDS): follow-up AML and survival
results of a randomized, double-blind, placebo (PBO)-controlled
study. ASH Annual Meeting Abstracts 2012; 120: 421.
159 Lim ZY, Killick S, Germing U, et al. Low IPSS score and bone
marrow hypocellularity in MDS patients predict hematological
responses to antithymocyte globulin. Leukemia 2007; 21: 1436–41.
160 Broliden PA, Dahl IM, Hast R, et al. Antithymocyte globulin and
cyclosporine A as combination therapy for low-risk non-
sideroblastic myelodysplastic syndromes. Haematologica 2006;
91: 667–70.
www.thelancet.com Vol 383 June 28, 2014