A JH

CME Information: Annual Clinical Updates 2015:

Myelodysplastic Syndromes
CME Editor: Ayalew Tefferi, M.D. and Author: Guillermo Garcia-Manero, M.D.

If you wish to receive credit for this activity, please refer to the website: www.wileyhealthlearning.com

Accreditation and Designation Statement

Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical
education for physicians.
Blackwell Futura Media Services designates this journal-based CME for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should
only claim credit commensurate with the extent of their participation in the activity.

Educational Objectives
Upon completion of this educational activity, participants will be better able to:

1. Understand the latest updates on molecular and cytogenetic alterations in Myelodysplastic Syndromes.
2. Understand the latest updates on the classification and treatment of patients with Myelodysplastic Syndromes.

Activity Disclosures
No commercial support has been accepted related to the development or publication of this activity.
CME Editor: Ayalew Tefferi, M.D. has no relevant financial relationships to disclose.
Author: Guillermo Garcia-Manero, M.D. has no relevant financial relationships to disclose.
This activity underwent peer review in line with the standards of editorial integrity and publication ethics maintained by American Journal of
Hematology. The peer reviewers have no conflicts of interest to disclose. The peer review process for American Journal of Hematology is single
blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review.
Conflicts of interest have been identified and resolved in accordance with Blackwell Futura Media Servicess Policy on Activity Disclosure and
Conflict of Interest. The primary resolution method used was peer review and review by a non-conflicted expert.

Instructions on Receiving Credit

This activity is intended for physicians. For information on applicability and acceptance of continuing medical education credit for this activity,
please consult your professional licensing board.
This activity is designed to be completed within one hour; physicians should claim only those credits that reflect the time actually spent in the
activity. To successfully earn credit, participants must complete the activity during the valid credit period, which is up to two years from initial
publication. Additionally, up to 3 attempts and a score of 70% or better is needed to pass the post test.
Follow these steps to earn credit:

 Log on to www.wileyhealthlearning.com
 Read the target audience, educational objectives, and activity disclosures.
 Read the activity contents in print or online format.
 Reflect on the activity contents.
 Access the CME Exam, and choose the best answer to each question.
 Complete the required evaluation component of the activity.
 Claim your Certificate.

This activity will be available for CME credit for twelve months following its launch date. At that time, it will be reviewed and potentially
updated and extended for an additional twelve months.

C 2015 Wiley Periodicals, Inc.

V

American Journal of Hematology, Vol. 90, No. 9, September 2015 831

ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
A JH
Myelodysplastic syndromes: 2015 Update on diagnosis,
risk-stratification and management
Guillermo Garcia-Manero*

Disease overview: The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid
disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute
myelogenous leukemia (AML). MDS occurs more frequently in older males and in individuals with prior
exposure to cytotoxic therapy.
Diagnosis: Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a
bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow
cytometry, or molecular genetics is complementary but not diagnostic.
Risk-stratification: Prognosis of patients with MDS can be calculated using a number of scoring systems. In
general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the
bone marrow, and cytogenetic characteristics. The most commonly used system still is probably the
International Prognostic Scoring System (IPSS). IPSS is being replaced by the new revised score IPSS-R.
Risk-adapted therapy: Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts,
and more recently cytogenetic and mutational profiles. Goals of therapy are different in lower risk patients
than in higher risk. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk
disease or AML, as well as to improve survival. In higher risk, the goal is to prolong survival. Current
available therapies include growth factor support, lenalidomide, hypomethylating agents, intensive
chemotherapy, and allogeneic stem cell transplantation. The use of lenalidomide has significant clinical
activity in patients with lower risk disease, anemia, and a chromosome 5 alteration. 5-Azacitidine and
decitabine have activity in higher risk MDS. 5-Azacitidine has been shown to improve survival in higher risk
MDS. A number of new molecular lesions have been described in MDS that may serve as new therapeutic
targets or aid in the selection of currently available agents. Additional supportive care measures may
include the use of prophylactic antibiotics and iron chelation.
Management of progressive or refractory disease: At the present time there are no approved interventions
for patients with progressive or refractory disease particularly after hypomethylating based therapy. Options
include participation in a clinical trial or cytarabine based therapy and stem cell transplantation.
Am. J. Hematol. 90:832841, 2015. V C 2015 Wiley Periodicals, Inc.

Disease Overview
MDS comprises a very heterogeneous group of myeloid malignancies with very distinct natural histories [13]. MDS occurs in three to four
individuals per 105 in the US population [4]. Prevalence increases with age. For instance, in individuals age 60 and above, prevalence is 735 per
105 [4]. Other series have reported higher rates [5]. MDS affects more frequently males than females [4]. Exposure to prior chemo or radiation
therapy is a risk for the development of MDS.
MDS is usually suspected by the presence of cytopenia on a routine analysis of peripheral blood. This prompts evaluation of bone marrow cell mor-
phology (aspirate) and cellularity (biopsy). A manual count of bone marrow blasts is fundamental for risk assessment. Cytogenetic analysis helps in pre-
dicting risk and in selecting therapy. Once this information is collected, the risk of the patient can be calculated. At the present time, the International
Prognostic Scoring System (IPSS) [6] is still commonly used. Natural history and therapeutic decisions are different for patients with lower risk disease
(low and INT-1) versus those with higher (INT-2 and high). In lower risk, disease interventions have been traditionally developed to improve transfu-
sion needs; whereas higher risk options were initially modeled following therapy of AML with remission induction being the goal. This concept was
modified by the better understanding of the natural history of MDS and the development of new therapies, in particular the hypomethylating agents.
Another important concept is that a large majority of patients with MDS die from causes intrinsic to the disease and not because of progression to
AML [7]. This has important implications for the development of therapies in MDS. The revised IPSS score (IPSS-R) was published in 2012 [8]. This

Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas

Conflict of interest: Nothing to report
*Correspondence to: Guillermo Garcia-Manero MD, Department of Leukemia MD Anderson Cancer Center Box 428 1515 Holcombe Blvd Houston, TX
77030. E-mail: ggarciam@mdanderson.org
Contract grant sponsor: Cancer Prevention & Research Institute of Texas; Contract grant number: RP100202.
Contract grant sponsors: Dr. Kenneth B. McCredie Chair in Clinical Leukemia Research endowment, Edward P. Evans Foundation, and the Fundacion Ramon
Areces.
Received for publication: 22 June 2015; Accepted: 24 June 2015
Am. J. Hematol. 90:832841, 2015.
Published online: in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/ajh.24102

C 2015 Wiley Periodicals, Inc.

V

832 American Journal of Hematology, Vol. 90, No. 9, September 2015 doi:10.1002/ajh.24102
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
Figure 1. Cytogenetic classification of MDS. Adapted from Schanz et al. [9]. [Color figure can be viewed in the online issue, which is available at wileyonline-
library.com.]
score includes a new cytogenetic risk classification of that divides
patients into five cytogenetic categories (Fig. 1) [810]. The IPSS-R
divides patients in five risk subgroups including an intermediate group.
Because current therapies were approved using either FAB or IPSS crite-
ria, I still use IPSS to decide therapy but IPSS-R to calculate prognosis.
Diagnosis
The diagnosis of MDS is generally suspected based on the presence
of an abnormal CBC. Diagnosis is confirmed by performing a bone
marrow aspiration and biopsy. Both procedures provide different
information. The bone marrow aspirate allows for detailed evaluation
of cellular morphology and evaluation of percent of blasts. The bone
marrow biopsy allows for determination of bone marrow cellularity
and architecture. Diagnosis is established by the presence of dysplasia.
A number of morphological classifications are in place to classify
patients with MDS. The most recent one being the 2008 WHO ver-
sion [11]. There is some controversy regarding the utility of bone
marrow biopsy. We believe that biopsy helps in diagnosis and poten-
tially in selecting therapy. For instance, in my practice we only use
immunotherapy (ATG, cyclosporine, and steroids) in hypocellular
MDS (marrow cellularity less than 20%30% depending on age). Cel-
lularity is better assessed by bone marrow biopsy.
A number of additional tests are needed to complete the laboratory
evaluation of a patient with MDS, most important of which is the analy-
sis of bone marrow cytogenetics. It is well established that cytogenetic
patterns are very heterogeneous in MDS [12]. Cytogenetics are of
importance to calculate prognosis of patients and in some subsets of
patients to select the most effective form therapy. The most recent cyto-
genetic risk classification in MDS includes five different subgroups
including 20 different alterations (Fig. 1) [9]. Recent data has indicated
that cytogenetic patterns are not stable in MDS and that a significant
fraction of patients acquired additional cytogenetic changes. This phe-
doi:10.1002/ajh.24102
Myelodysplastic Syndromes: 2015 Update
nomenon is associated with increased risk of transformation to AML
and worse survival [13]. This data has implications for the follow up of
patients at risk for clonal cytogenetic acquisition.
A number of other assays can be used to help in the diagnosis of
MDS. These include the use of flow cytometry and fluorescent in situ
hybridization (FISH). Flow cytometry can help in the identification of
abnormal phenotypic patterns and can be of help in cases of minimal
dysplasia. Because the significant heterogeneity of cytogenetic altera-
tions in MDS, there is no evidence that a panel of FISH probes could
replace routine 20 metaphase cytogenetic analysis. Thus, in my opinion
FISH and flow cytometry should not be considered part of the standard
work up evaluation procedure of the patient with MDS and should be
used in specific situations. More recently, and thanks to the discovery of
multiple genetic mutations in MDS, we now have access to clinical tools
for molecular annotation of patients with MDS.
Diagnostic problems in MDS
Because diagnosis of MDS is based on morphological assessment it
can be subjective particularly in patients with early low risk disease. It is
calculated that diagnostic discrepancy can occur at the time of initial
presentation in close to 20% of patients [14]. This has obvious implica-
tions for therapeutic decision making and patient counseling. In gen-
eral, diagnosis is obvious in patients with excess blasts. The problem is
in patients without excess blasts where diagnosis is based on dysplasia.
Clinical assessment is needed in patients with minimal or not diagnostic
evidence of dysplasia. In these cases, it is recommended that other
causes of cytopenia be excluded. Routine tests include the analysis of
anemia and thrombocytopenia, and exclusion of cause of blood loss or
inflammatory processes. When suspected, evaluation of GI tract needs
to be considered. Once other potential causes of cytopenia are excluded,
patients with cytopenia but no dysplasia are considered in the subset of
idiopathic cytopenia of unknown significance (ICUS). A fraction of
these patients may have cytogenetic abnormalities. The natural history
American Journal of Hematology, Vol. 90, No. 9, September 2015 833
Garcia-Manero ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

TABLE I. The Global MDACC MDS Prognostic Model [19]

TABLE II. MDACC MDS Lower Risk Prognostic Model [20].
Prognostic factor Points
Characteristics Points
PS  2 2
Age Unfavorable cytogenetics 1
6064 1 Age  60 years 2
>64 2 Hemoglobin < 10 (g/dL) 1
Platelets x109/L Platelets
<30 3 < 50 x 109/L 2
30-49 2 50200 x 109/L 1
50199 1 Bone Marrow Blasts  4% 1
Hemoglobin <12 g/dL 2 Score Median survival 4-year OS (%)
BM blast % 0 NR 78
5 to 10 1 1 83 82
11 to 19 2 2 51 51
WBC > 20 x109/L 2 3 36 40
Alteration of chromosome 7 or  3 alterations 3 4 22 27
Prior transfusion 1 5 14 9
6 16 7
Abbreviations: PS, performance status; BM, bone marrow; WBC, white 7 9 N/A
blood cell count.
Patients with 0 to 4 points had a median survival of 54 months and a 3- Characteristics were selected from multivariate analysis model in patients
year 63% survival. Patients with 5 and 6 points had a median survival of with lower risk MDS. Each characteristic is associated with a number of
23 to 30 months and 3-year survival of 30% to 40%. Patients with 7 to 8 points. Score is calculated by adding all points. Each score allows calcula-
points had a median survival of 13 months and a 3-year survival rate of tion of median survival (in months) and probability of survival at 4 years.
13% to 19%. Patients with 9 or more points had a median survival of 5 to Adapted from Ref. 20.
10 months and a 2% 3-year survival. Adapted from Ref. 19.

of this group of patients with ICUS is not well known and observation
is recommended at the present time. Recently, the presence of clonal
somatic mutations have been reported in hematopoietic cells from
older individuals without evidence of hematological disorder [15,16].
Patients with evidence of clonal hematopoiesis are at an increased risk
to develop MDS [16]. The clinical implications of these findings are
not understood at this point [17].
Finally, a subset of patients of importance are those with MDS/
MPN features. These are patients with evidence of a myeloprolifera-
tive component (with or without fibrosis). At the present time, we do
not fully understand the natural history of patients with MDS/MPN
[18]. In our center they are currently treated as MDS, but studies are
ongoing to clarify this issue.
Risk Stratification
The prognosis of patients with MDS is very heterogeneous and
thus the need to develop prognostic systems that allow risk stratifica-
tion and help in the timing and choice of therapy. Apart from the
intrinsic prognostic value of morphological classifications [11], a
number of prognostic scores are currently in use in MDS. The IPSS
[6] has been in place since 1997. The prognostic score includes per-
cent of blasts, number of cytopenias and cytogenetics. IPSS is of fun-
damental importance as it has allowed the prognostication of patients
for over two decades. This system is highly reproducible and very
simple to use. The system has several limitations that have become
evident over the years. The most important one is that it is not a
very precise predictor of prognosis in patients with lower risk disease
and that it attributes relatively little weight to cytogenetics. The IPSS-
R includes different cut off points of cytopenias and incorporates the
new cytogenetic MDS score [8]. IPSS-R should be the standard tool
to assess risk although limitations still exist for its use as no drug
therapy has been approved yet using IPSS-R. A new molecular IPSS
system is expected soon.
Both the IPSS and IPSS-R were developed in a very specific subset
of patients: newly diagnosed patients at the time of initial presentation.
Patients with proliferative features and CMML or that have received
prior therapy were excluded [6]. To overcome these limitations, the
global MDACC model was developed [19]. This model is summarized
in Table I. The importance of the global MDACC model is that allows
evaluation of all patients that are considered as MDS at any time dur-
ing their course of their disease without needed WHO evaluation.
It has also become apparent that the natural history of patients
with lower risk disease is very heterogeneous [20]. We evaluated
outcomes in a large series of patients with low or int-1 disease by
IPSS. We found that prognosis varied significantly in patients with
lower risk MDS and were able to develop a lower risk MDS specific
prognostic score (Table II). This has significant implications for the
development of specific interventions for patients with lower risk
disease. This model has been validated on several occasions and it
is being used to identify patients with poor prognosis lower risk
disease that could be candidates for early intervention. Bejar et al.
[21] published data indicating that patients with poorer prognosis
and lower risk disease accumulate a higher number of mutational
events than the better risk counterpart. This data provides a poten-
tial molecular basis for the identification of this group of patients
and poorer prognosis.
MDS occurs in older patients that suffer from comorbidities more
frequently. None of the systems discussed above include impact of
comorbidity to the calculation of the natural history of MDS patients.
To study this issue, we used a comprehensive comorbidity score
known as ACE-27in a cohort of 500 patients with MDS [22]. Pres-
ence of comorbidity had a significant independent impact on survival
and a prognostic score could be developed that included age, IPSS,
and ACE-27 score. This data indicates the need to add comorbidity
scores in MDS. Recently, other groups have confirmed the impor-
tance of comorbidity scores in MDS [23]. We recently confirmed that
ACE-27 adds to the prognostic value of IPSS-R [24].
Additional prognostic scoring systems include systems for hypocel-
lular MDS [25] and for therapy related MDS [26]. It should be noted
that prognosis in t-MDS is strongly associated with presence of cyto-
genetic alterations: diploid patients have prognosis not dissimilar to
that of de novo patients [26].
Cytogenetic and Molecular Alterations
Over the last 36 months, a number of very important studies have
been published describing comprehensive analysis of the incidence
and clinical impact of multiple genetic lesions in MDS [27]. Bejar
et al. [28] first published an analysis of 18 genes using different

834 American Journal of Hematology, Vol. 90, No. 9, September 2015 doi:10.1002/ajh.24102
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES Myelodysplastic Syndromes: 2015 Update

TABLE III. Reported Frequency of Genetic Lesions in MDS [28,3032]

Gene % Location Function

SF3B1 28 2q33 Splicing factor

TET2 21 4q24 Control of cytosine hydroxymethylation
ASXL1 14 20q11 Epigenetic regulator
SRSF2 12 17q25 Splicing factor
RUNX1 9 21q22 Transcription factor
TP53 8 17p13 Transcription factor
U2AF1 7 21q22 Splicing factor
EZH2 6 7q36 Polycomb group protein
NRAS 4 1p13 Signal transduction
JAK2 3 9p24 Tyrosine kinase
ETV6 3 12p13 Transcription factor
CBL 2 11q23 Signal transduction
IDH2 2 15q26 Cell metabolism, epigenetic regulation
NPM1 2 5q35 Phosphoprotein
IDH1 1 2q33 As IDH1
Figure 2. Distribution of mutational events in MDS. Adapted from Papaem- KRAS <1 12p12 Signal transduction
manuil et al. [29]. [Color figure can be viewed in the online issue, which is GNAS <1 20q13 G protein
available at wileyonlinelibrary.com.] PTPN11 <1 12q24 Protein phosphatase
BRAF <1 7q34 Raf kinase
PTEN <1 10q23 Phosphatase
techniques on 439 patients. More recently, two major studies have CDKN2A <1 9q121 Cell cycle control
described the mutational landscape of MDS in larger series analyzing
more genes [29,33] (Fig. 2). For instance, a European consortium has
reported an analysis of mutations in 111 genes using next generation
sequencing technology in a cohort of 738 patients [29]. Frequency of
common mutations is shown in Table III. This emerging data will
have a significant impact not only on our ability to prognosticate
patients with MDS but also in potentially selecting therapy. For
instance, it has been reported that patients with TET2 mutations may
have higher response rates to azacitidine than those without mutation
[34,35]. In addition, the results of molecular mutations is aiding in
the development of clinical trials for instance for patients with IDH1,
IDH2, Flt-3, and RAS. Recently, very poor outcomes with allogeneic
stem cell transplantation have been associated with presence of p53
and DNMT3A mutations [36].
Figure 3. Proposed treatment algorithm of patients with MDS. Once diag-
Risk Adapted Therapy nosis is confirmed, patients are divided into a lower and a higher risk cat-
egory. Options for patients with lower risk disease include growth factors,
At the present time, we still use IPSS to decide the choice of ther- lenalidomide, and azanucleosides. Treatment in general is sequential:
apy for an individual patient. Below is a summary of options and rec- patients that do not respond to growth factors can be treated with lenali-
ommendations for specific subsets of patients [2]. A treatment domide or azanuclesoides, if appropriate. Patients that fail lenalidomide
can subsequently be treated with azanucleosides. There is little experi-
algorithm is shown in Fig. 3. ence in terms of outcomes with this approach. Patients that fail all three
therapies should be considered for alloSCT and/or clinical trial. For
Options for newly diagnosed patients with lower risk patients with higher risk MDS options are alloSCT, AML-like therapy, or aza-
MDS nucleoside. Prognosis of patients that fail any of these approaches is
poor, particularly for those exposed to azanucleosides. In this setting
Therapy in this subset of patients is based on the transfusion needs alloSCT and clinical trial should be strongly considered. [Color figure can
of the patients. Patients that are transfusion independent are usually be viewed in the online issue, which is available at wileyonlinelibrary.com.]
observed until they become transfusion dependent. Below is a
description of agents currently available for patients with lower risk
MDS. A new important concept in lower risk MDS is the idea of group also evaluated the impact of ESA on survival in a retrospective
early intervention in patients with poor prognosis lower risk MDS. study of 284 patients and compared it with a group of patients that
We are currently testing this concept in prospective clinical trials formed the IPSS cohort [41]. In this study patients treated with ESA had
using very low doses of hypomethylating agents. a better survival (HR for death was 0.43, 95% CI 0.25-0.72] [41]. Ques-
Erythroid growth factor support. The use of erythroid stimulating tions on potential tumorigenic effect of these drugs haves resulted in
agents (ESA) is common practice in community practice [37]. It should increased scrutiny of their use. G-CSF is not approved by the FDA for
be noted that no randomized study has ever proven than this interven- patients with anemia of MDS in the US.
tion positively affects the natural history of patients with MDS. A num- Recent data on the results with romiplostin [42] questions its use
ber of ESAs are available. Reported response rates range from 30% to in patients with lower risk MDS, particularly because of complications
60% depending on study [38]. Data from the Swedish group indicated related to disease transformation and marrow fibrosis. A number of
that addition of G-CSF to erythropoietin increases responses rates. In a studies are now evaluating eltrombopag in MDS, another TPO ago-
retrospective observational study, early introduction of this combina- nist, but results are not known at this point.
tion in patients with low risk disease and minimally transfusion depend-
ent patients had an impact on survival [39]. The Swedish group also Recommendation. I believe that a course of ESA with or without G-
developed an algorithm to predict response to ESA [40]. The French CSF is not contraindicated in most patients with low risk MDS with

doi:10.1002/ajh.24102 American Journal of Hematology, Vol. 90, No. 9, September 2015 835
Garcia-Manero
significant anemia without other cytopenia. Data indicates that early
incorporation of these agents is more effective. I maintain therapy for
at least 3 months to judge efficacy. In responding patients, I continue
therapy until transfusion effect is lost.
Lenalidomide. Lenalidomide is approved for patients with lower
risk MDS, anemia, and alteration of chromosome 5 [43]. Phase I results
[44] were confirmed in a subsequent phase II study of lenalidomide in
patients with anemia and alteration of chromosome 5 [44]. In that study
148 patients received 10 mg of lenalidomide for 21 days every 4 weeks
or daily. Of those, 112 had decrease need for transfusions (76%; 95% CI
6882) and 99 patients (67%; 95% CI, 5974) became transfusion inde-
pendent. Response was fast: median time 4.6 weeks. The median rise of
hemoglobin was 5.4 g/dL. Of interest, cytogenetic responses were
observed in close to 50% informative patients. Predictors of response
included presence of a platelet count of 100 3 109/L and less than four
prior units of red cells transfused. It should be noted that in this study
patients with a platelet count of less than 50 3 109/L were excluded.
Subsequently, these results were confirmed in a phase III known as
AZA-004 comparing two different doses of lenalidomide (5 and 10 mg
orally daily) versus placebo. This study was also designed to clarify the
issue of transformation to AML. Ten micrograms daily was the superior
arm and that there was no increased incidence of transformation to
AML in patients treated with lenalidomide [45]. Of importance, a recent
report from the initial MDS-003 trial of lenalidomide has indicated a
longer survival for patients responding to therapy [46]. This is addi-
tional evidence that lenalidomide can change the natural history of
patients with 5q- MDS.
In parallel, lenalidomide has been investigated in patients without
chromosome 5 alterations [47]. In an initial study, 214 patients
received lenalidomide 10 mg orally daily or 10 mg on days 1 to 21 of
a 28-day cycle. Fifty six (26%) patients achieved transfusion inde-
pendence after a median of 4.8 weeks of therapy. Median response
duration was 41 weeks. Preliminary results of a phase III trial in this
patient population were presented at ASH 2014 (Santini et al., unpub-
lished) and supported the findings of the initial phase II trial [47].
Recommendation. The degree of response with lenalidomide in
patients with lower risk MDS, anemia, good platelets, and del5q makes
it the standard of care for this subset of patients. This is further rein-
forced by the recent data on survival in responding patients [46]. I do
not consider this agent in patients with thrombocytopenia. No recom-
mendation can be made for patients without an alteration of chromo-
some 5 at the present time. It is likely that a subset of patients with
anemia, low risk disease, and diploid cytogenetics could also benefit
from this compound. This will be clarified with the full report the study
by Santini et al (ASH 2014, unpublished).
Azanucleosides. Two azanuclesoides are approved for MDS: 5-
azacitidine [48] and 5-aza-20 -deoxycitidine (decitabine) [49]. 5-Azacitidine
is approved for all subsets of MDS, whereas decitabine for those with INT-
1 disease and above. There is little data in the use of these compounds in
lower risk MDS. None of them have been shown to modify the natural
history of patients with lower risk disease.
Different schedules of 5-azacitidine have been explored in MDS. In
a community study a 5-day schedule was compared with a 7 day 5-2-
2 schedule (weekend off) or a 5-2-5 schedule of 10 days [50]. Fifty
patients were assigned to each arm (except 5-2-2 was 51 patients).
Most patients had lower risk disease. Hematologic improvement was
achieved by 44% to 56% of patients in each arm. Transfusion inde-
pendency was documented in 50% to 64% of patients. There was a
trend for better response rates and less toxicity with the 5-day sched-
ule of 5-azacitidine. Therefore it is reasonable to use a shorter (5-day
schedule) of 5-azacitidine in lower risk MDS. The results of a phase 1
trial of an oral derivative of azacitidine have been published [51].
Oral azacitidine is currently being studied in an international phase
836 American Journal of Hematology, Vol. 90, No. 9, September 2015
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
III trial in patients with lower risk MDS and significant cytopenias
(NCT01566695).
There is relatively little data with decitabine in patients with lower
risk disease. In the initial randomized trial of decitabine [49], 31
patients with INT-1 disease were treated. Four of the 28 patients
achieved some type of response. A randomized phase II trial was con-
ducted exploring a 3-day subcutaneous schedule versus a weekly 3 3
monthly schedule. This study did not find significant differences
between both arms, although it declared the daily 3 3 schedule as an
initial winner. Low dose decitabine used in this fashion was associ-
ated with close to 60% trilineage transfusion independence with mini-
mal hematopoietic toxicity [52].
Recommendation. Both 5-azacitidine and decitabine are used in the
US in patients with lower risk disease that are transfusion dependent.
Most patients treated with these agents have failed or were not candi-
dates for growth factor support or lenalidomide. Further studies of
these agents in lower risk MDS are needed. An oral formulation of 5-
azacitidine is being studied for patients with lower risk MDS [[51]].
Lower dose of azacitidine or decitabine can be considered for these
patients.
Immune therapy. This is an area of controversy. It is accepted that
a subset of patients with MDS are characterized by deregulation of both
cellular and innate immunity [5355]. Based on this, it will be logical
that the use of immune-modulatory agents could have therapeutic bene-
fit in MDS. The NIH group pioneered these approaches. Agents studied
include antithymocyte globulin (ATG), cyclosporine, and steroids.
These therapies have been modeled after therapy of aplastic anemia
[53]. The NIH group also developed an algorithm to predict response to
these classes of agents [[56]]. This model included younger age, HLA-
DR15 positivity, and shorter duration of transfusion dependency. Using
this algorithm, the NIH group reported that alemtuzumab, an antibody
against CD52, has significant activity in patients with MDS predicted to
respond to immune suppressive therapy [57]. The group at Moffitt Can-
cer Center has suggested that a CD4/CD8 ratio could also be used to
predict response [58]. Our group has not been capable to reproduce
some of the data discussed above. Response rates with ATG observed at
MDACC are significantly lower than those of the NIH [59]. The most
important predictor for response for us has been the presence of mar-
row hypocellularity [60]. This is consistent with the results of Mufti and
coworkers in London [61].
Also recently the impact of ATG based therapy on survival has
been questioned. Data from a Swiss study comparing ATG versus
supportive care indicated a higher response rate, but no survival ben-
efit [62]. In this study, patients were randomized to a combination of
horse ATG with cyclosporine versus best supportive care (BSC).
Forty-five patients received ATG1CSA and 43 patients received BSC.
By month 6, 13 of the 45 patients on ATG1CSA had a hematologic
response compared with four of the 43 patients on BSC (P 5 0.0156).
Despite higher response rates no significant effect on survival or
transformation was observed.
Recently, the NIH group has also reported on the clinical activity
of eltrombopag in patients with aplastic anemia as salvage therapy
[63]. This data was of importance because of the fact that responses
were multilineage and not just restricted to platelets. A number of
studies are investigating this agent in MDS.
Recommendation. This is a particular difficult group of patients. A
majority of older patients cannot tolerate ATG and most patients are
treated with some form of supportive care that could include cyclospo-
rine, growth factors, and steroids. The impact of it is not known either.
In younger patients with severe hypoplastic MDS, allogeneic stem cell
transplantation (alloSCT) should be considered as soon as possible. For
those that are not candidates, a combination with horse ATG is
doi:10.1002/ajh.24102
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES Myelodysplastic Syndromes: 2015 Update

Figure 4. Impact on survival of stem cell transplantation in MDS. Adapted from Koreth et al. [65]. A: Monte Carlo analysis for low/intermediate-1 international
prognostic scoring system (IPSS) myelodysplastic syndromes (MDS). Simulated Kaplan-Meier survival plots (n 5 10,000; with log-rank P value) are indicated
for the modeled 10-year time period, comparing a strategy of early reduced-intensity conditioning (RIC) transplantation (blue line) versus no early RIC trans-
plantation (gold line). The results graphically indicate survival benefit of the nontransplantation strategy in low/intermediate-1 IPSS MDS quality-adjusted life
expectancy (QALE): two-way sensitivity analysis. B: Two-way sensitivity analysis plot for the utilities of the Markov states alive after RIC transplantation and
alive with MDS without RIC transplantation is shown. The gold area indicates the range in which nontransplantation therapy produces superior QALE. The
blue area indicates the range in which RIC transplantation produces superior QALE. The red square indicates the plausible range of quality of life (QoL) for
alive with low/intermediate-1 IPSS MDS and for alive after RIC transplantation and does not cross the threshold line. This result is interpreted as insensi-
tive, that is, the conclusion regarding benefit does not change within the plausible QoL range. C: Monte Carlo analysis for intermediate-2/high IPSS MDS.
Simulated Kaplan-Meier survival plots (n 5 10,000; with log-rank P value) are indicated for the modeled 10-year time period, comparing a strategy of early
RIC transplantation (blue line) versus no early RIC transplantation (gold line). The results graphically indicate survival benefit of the early RIC transplantation
strategy in intermediate-2/high IPSS MDS. D: Intermediate-2/high IPSS MDS QALE: two-way sensitivity analysis. Two-way sensitivity plot for the utilities of the
Markov states alive after RIC transplantation and alive with MDS without early RIC transplantation is shown. The gold area indicates the range in which
nontransplantation therapy produces superior QALE. The blue area indicates the range in which RIC transplantation produces superior QALE. The red square
indicates the plausible range of QoL for alive with intermediate-2/high IPSS MDS and for alive after RIC transplantation and does not cross the threshold
line. This result is interpreted as insensitive, that is, the conclusion regarding benefit does not change within the plausible QoL range. HCT, hematopoietic
cell transplantation. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

recommended. I cannot recommend the use of alemtuzumab at the
present time until more data from other clinical trials is reported. The
data on eltrombopag is of interest.
Allogeneic stem cell transplantation. AlloSCT is usually not recom-
mended in patients with lower risk disease even if they are young. This
is based on data from Cutler et al. using a Markov model [64]. The
anticipated early mortality with alloSCT cannot be overcome by the
potential beneficial survival effect of alloSCT. This concept was con-
firmed by Koreth et al. at recently (Fig. 4) [65]. Using another Markov
model, the investigators analyzed the impact of reduced intensity trans-
plant in older patients with MDS. Patients with lower risk disease did
not benefit from this less toxic transplant approach [65].
Recommendation. I generally do not recommend alloSCT in patients
with lower risk disease at initial presentation. That said because of
time required for donor identification, I refer all potential candidate
patients for a transplant consult in anticipation of future needs.
Patients that are candidates for alloSCT and that had been exposed to
multiple therapies (growth factors, lenalidomide, azanuclesoides, etc.)
should be considered for transplantation. These patients are also candi-
dates for clinical trials. Patients with hypoplastic MDS that are young
should be considered for alloSCT up front.
Supportive care measures in MDS. A number of interventions can
be used in patients with MDS. These include the use of prophylactic
antibiotics and iron chelation. No randomized data exists to make
formal recommendation for any of these interventions. In my experi-
ence patients with isolated neutropenia and MDS not receiving ther-
apy are not at significantly increased risk of infection to support
recommendation of prophylactic antibiotics. Prophylactic antibiotics
are commonly used in the context of active therapy for these
patients.
The role of iron chelation in MDS is more complicated. Data from
thallasemias indicates that iron chelation has an important role in
this setting. Iron accumulation is frequent in MDS. The consequences
of this are not fully understood in MDS. I do not see in my practice
patients with MDS and iron deposition that develop liver cirrhosis or
cardiomyopathy as frequently as reported by other groups [66]. Iron
accumulation could have a role in transformation to AML [67] and
in the increased risk of infectious complications known to occur on
these patients. The NCCN guidelines recommend the use of chelation
therapy in patients with ferritin levels above 2500 ng/mL [68]. A large
phase III (NCT00940602) study is evaluating the role of iron chela-
tion in MDS.
Recommendations. I do not routinely recommend antibiotics in
patients with isolated neutropenia and MDS that are not receiving
some form of cytotoxic or immunosuppressive therapy. I use prophylac-
tic antibiotics in patients receiving active therapy. I use iron chelation
in patients with ferritin levels in excess of 2500 ng/mL but I consider
all these patients for a clinical trial of iron chelation.

doi:10.1002/ajh.24102 American Journal of Hematology, Vol. 90, No. 9, September 2015 837
Garcia-Manero
Options for patients with relapsed or refractory lower
risk MDS and investigational new agents in lower risk
MDS
Treatment of patients with lower risk MDS is sequential. A com-
mon practice is to start growth factor support and then consider
lenalidomide or an azanucleoside. Patients that fail either lenalido-
mide or azanucleoside are candidates for clinical trials or alloSCT.
There is no drug approved in the US for patients with MDS and
HMA failure. Recently the survival of these patients was calculated to
be between 14 and 17 months [69].
A number of agents are being studied for lower risk MDS. These
include oral azacitidine [51] and oral decitabine, agents that modulate
TGF-B pathway such as ACE-536 and ACE-011 [70,71], proteasome
inhibitors and antagonists of toll-like receptor signaling [55,72].
Options for newly diagnosed patients with higher risk
MDS
Options for patients with higher risk MDS have evolved signifi-
cantly over the last decade. Before that period most patients were
treated with some of cytarabine based therapy modeled after AML.
The used of azanucleosides has modified this practice [2].
Azanucleosides. Decitabine was studied in an initial randomized
comparing it to BSC [49]. In this study the dose of decitabine was
15 mg/m2 IV infused over 3 hours every 8 hours for 3 days (at a
dose of 135 mg/m2 per course) and repeated every 6 weeks. Although
there was no clear benefit in terms of survival in this study, the use
of decitabine was associated with a complete response rate of 9% and
overall response rate of 17%. These results led to the approval of dec-
itabine in the US. Based on the results of a phase I trial of decitabine
performed at MDACC, a Bayesian randomized phase II trial of three
different doses and schedules of decitabine was conducted [73]. In
this study, a 5-day schedule of decitabine administered daily at a dose
of 20 mg/m2 was shown to be superior to a 10-day or subcutaneous
schedule. A multicenter phase II trial of decitabine (ADOPT) using
the 5-day schedule confirmed the safety of this schedule, although
response rates were lower than those reported by the MDACC [74].
In the ADOPT study the median number of courses administered
was five, the CR rate was 17% and the median survival was 19.4
months. No randomized survival study of a 5-day schedule of decita-
bine has been conducted in MDS. In parallel with this work, Euro-
pean investigators developed a randomized study of decitabine using
the initial 3-day schedule. The major objective of the study was sur-
vival. Unfortunately, use of decitabine at this dose and schedule was
not associated with improved survival in patients with higher risk
MDS [75]. Despite all this data, the final dose and schedule of decita-
bine is not fully understood. Blum et al. have indicated that a 10-day
schedule of decitabine has significant activity in AML [76].
5-Azacitidine has been studied in higher-risk MDS in two major
randomized multicenter trials: CALGB 9221 [77] and AZA-001 [48].
In the CALGB 9221 [77] study, 191 patients with MDS were random-
ized between 5-azacitidine (75 mg/m2/day for 7 consecutive days
every 28 days) and best supportive care (BSC). Median age was 68
years. Sixty percent of the patients in the 5-azacitidine group, com-
pared with 5% of control arm patients, responded to treatment
(P < 0.0001). The median time to leukemic transformation or death
was 21 months in patients treated with 5-azacitidine versus 12
months in the BSC arm (P 5 0.007). No significant difference in sur-
vival was observed. A landmark analysis suggested a survival advant-
age for patients initially on 5-azacitidine or who had crossed-over to
5-azacitidine within 6 months of inclusion on study (P 5 0.03). A sig-
nificant improvement in quality of life was documented in patients
treated with 5-azacitidine compared with BSC [78]. AZA-001 was a
randomized study designed to test the concept that treatment with 5-
838 American Journal of Hematology, Vol. 90, No. 9, September 2015
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
azacitidine resulted in improved survival compared with a menu of
standard of care options [48]. These included BSC, low dose cytara-
bine (ara-C) or AML-like therapy. In AZA-001, 358 patients with
higher-risk MDS were randomized to either 5-azacitidine (as per
CALGB9221 schedule) or to standard of care. Median age of patients
was 69 years. Median survival was significantly better in patients
treated with 5-azacitidine versus standard of care options: 24.5
months versus 15 months (P 5 0.0001). Progression to AML was sig-
nificantly delayed, and RBC transfusion requirements and rate of
infections were also significantly improved with 5-azacitidine. The
survival advantage with 5-azacitidine was irrespective of age (includ-
ing patients older than 75 years), percent of marrow blasts (including
patients with 20%30% blasts, now classified as AML using WHO
criteria) or karyotype. This effect was significant when compared with
BSC and low dose ara-C. The number of patients treated with AML-
like therapy was too small to allow comparison with 5-azacitidine.
Biomarkers of response to azanucleosides. An area of active
research is the identification of biomarkers predictive of response to
azanucleosides. Due to their capacity to induce DNA hypomethyla-
tion, a number of groups have focused in the identification of methyl-
ation patterns that would predict for response. Recently, a large-scale
methylation analysis has resulted in the identification of 167 differen-
tially methylated regions associated with response to hypomethylating
agent based therapy [79]. Of interest, most of these regions were
localized in nonpromoter regions. Two candidate biomarkers and a
clinical model have been proposed. Levels of miR29b [76] and muta-
tions on TET2 [80] have been reported to be associated with response
to decitabine and azacitidine respectively. miR29b regulates expres-
sion levels of DNMT1 [76]. TET2 is a protein involved in the conver-
sion of 5mC to 5OHmC and could therefore have resulted in passive
induction of DNA methylation [81]. None of these two biomarkers
have been confirmed in other larger studies. Our group was not able
to correlate miRNA29b levels with response [82]. The French group
reported that previous low dose ara-C, bone marrow blasts more
than 15% and abnormal karyotype predicted for lower response rate
to 5-azacitidine [83]. Poor performance status, intermediate and poor
risk cytogenetics, circulating blasts, and more than four units of red
blood cells transfuse every 8 weeks were associated with worse sur-
vival [83]. In the near future a combination of genetic and clinical
markers could be used to define who may benefit from this type of
therapy. The incorporation of new molecular markers is going to
have a profound impact on our ability to prognosticate and select
therapy for patients with MDS.
Recommendation. The azanucleosides are the standard of care for
most patients with higher risk disease. No study has compared 5-
azacitidine vs decitabine. Although response rates appear to be similar,
only 5-azacitidine has been associated with improvement of survival in
a randomized trial. Based on this, I consider 5-azacitidine standard
therapy for front line treatment in higher risk MDS.
AML-like chemotherapy. AML-like protocols in higher risk MDS
have generally used classical anthracycline-araC combinations similar
to those used in de novo AML [84,85]. When used in MDS or AML
post-MDS, AML-like therapy results in lower CR rates (40 to 60%),
shorter CR duration (median duration of 10 to 12 months) and tend
to be associated with more prolonged periods of aplasia than
observed in AML. In addition, the feasibility of AML-like therapy is
also reduced by the advanced median age of patients with MDS. The
most important prognostic factor of response to AML-like therapy is
karyotype: patients with unfavorable karyotype (27/del 7q or com-
plex karyotype) have a low CR rate and short duration of response.
This is of importance as, at least in the AZA-001 study [48], patients
with alterations of chromosome 7 had a significant benefit with 5-
azacitidine versus other therapies. Currently, AML-like therapy is
doi:10.1002/ajh.24102
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
Figure 5. Impact on survival of mutation of p53 or DNMT3A in patients with MDS treated with allogeneic stem cell transplantation (adapted from Bejar et al.
[36]). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
only recommended for relatively younger patients with favorable
karyotype that are candidates for alloSCT.
Recommendation. The randomized AZA-001 study was not powered
to demonstrate the superiority of 5-azacitidine versus AML-like ther-
apy. The reason for this being that most investigators did not consider
their patients candidates for such therapy. Therefore the question is
who may be a candidate for AML therapy. In our practice this is
restricted to younger patients with a high likelihood of response to the
therapy, such as diploid patients or candidates for alloSCT. I rarely use
AML therapy in older patients or in those with poor risk cytogenetics.
AlloSCT. AlloSCT is reported to be the only curative treatment of
higher-risk MDS. Results from selected studies report prolonged DFS
in about 30%50% of the patients [86]. However its use is mainly
restricted to younger patients with an appropriate donor. Different
transplant modalities of different intensities and donor sources are
now in use. Most of them remain investigational and therefore in my
opinion all patients should be transplanted in the setting of a clinical
trial. Current advances in transplant technology are allowing the con-
sideration of older patients and alternative donors. This should result
in greater number of older patients benefitting from this potentially
curative treatment modality.
There are several relevant practical questions regarding alloSCT in
MDS. These include timing of transplant; and what to do with
patients that achieved a complete response to hypomethylating agent
prior to alloSCT. A study from the IBMTR indicated that early trans-
plantation in higher-risk MDS was associated with longer life expect-
ancy [64,65] (Fig. 4). Although data suggests longer survival with
SCT in patients with higher risk disease, it should be noted that
curves cross close to 3 years after initiation of therapy when com-
pared with hypomethylating agents. It will be important to identify
who are long-term survivors that benefit the most from transplant. A
prospective study is comparing azanucleosides use versus transplant
in MDS. In terms of what to do in responding patients, no recom-
mendation can be given at this time. Other questions include whether
or not alloSCT should be preceded by a cytoreductive regimen (with
chemotherapy or perhaps hypomethylating agents). Many authors
doi:10.1002/ajh.24102
Myelodysplastic Syndromes: 2015 Update
consider that when marrow blasts > 10% at the time of transplant,
because of the very high relapse risk post transplant, pretransplant
therapy is required. A recent report from the EBMTR has indicated
that long-term survival of patients with monosomy 7 is very poor
with alloSCT [87]. Although this data needs to be validated in more
recent series, these results have significant implications for the use of
alloSCT in MDS, as this suggests that the current practice of reserv-
ing transplant for poor prognostic features may not be indicated. In
patients at higher risk for relapsed post alloSCT, data from a single
arm trial indicated that post-transplant hypomethylating use can
improve outcome [88].
To complicate more the decision making regarding alloSCT in
MDS, a recent report has associated presence of p53 and DNMT3A
mutations with poor prognosis. At this time no consensus exists in
terms of how to use this data [36] (Fig. 5).
Recommendations. All patients potential candidates for alloSCT
should be counseled regarding the possibilities of undergoing alloSCT.
Optimally patients will be enrolled in an MDS specific clinical trial of
alloSCT. A national study to study this issue is being developed. I con-
sider the use of lower doses of 5-azacitidine in patients at high risk for
relapse post transplantation, including more recently now those with
higher risk mutations such as p53 or DNMT3A.
Investigational new options for patients with higher
risk MDS, including HMA failures
Because the HMAs are the standard of care in front line higher
risk MDS, a number of studies are being conducted to test combina-
tions. Agents used in combinations include the histone deacetylase
inhibitors [89,90] and lenalidomide. So far none of these combina-
tions have been shown to be superior to single agent HMA. A second
generation HMA known as SGI-110 is currently under development.
SGI-110 is a dinucleotide form of decitabine.
At the present time there is no therapy approved for patients with
higher risk MDS that fail hypomethylating agents or relapsed after
AML-like therapy or alloSCT. The group of patients that failed
American Journal of Hematology, Vol. 90, No. 9, September 2015 839
Garcia-Manero ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

hypomethylating agents has particularly poor prognosis with an esti-
mated survival of 46 months [91]. This is an area of active research
that is complicated by lack of understanding of the mechanisms of
resistance to HMAs. It also should be emphasized that outcomes of
patients in response to HMA that electively stopped HMA is poor
[92]. In a phase III study of rigorsetib (Garcia-Manero, ASH 2014,
unpublished) versus best supportive care, the study drug was not
shown to improve survival. Very low dose clofarabine may have a
role in patients with HMA failure and diploid cytogenetics (Jabbour,
ASH 2014, unpublished). A recent area of particular interest is the
use of immune checkpoint inhibitors in MDS [93]. Multiple studies
are investigating the role of this new class of agents in MDS. Finally,
it is becoming apparent that a fraction of patients with higher risk
MDS are characterized by targetable mutations such as Flt-3 [94],
RAS, and IDH1and IDH2. Multiple agents blocking these mutations
are currently under development [95].
Recommendations. All patients with higher risk disease that have
relapsed or refractory disease should be considered for an investiga-
tional clinical trial and potentially alloSCT.

REFERENCES 17. Steensma DP, Bejar R, Jaiswal S, et al. Clonal

1. Tefferi A, Vardiman JW. Myelodysplastic syn-
dromes. N Engl J Med 2009;361(19):18721885.
2. Garcia-Manero G, Fenaux P. Hypomethylating
agents and other novel strategies in myelodys-
plastic syndromes. J Clin Oncol 2011;29(10):516
523.
3. Garcia-Manero G. Myelodysplastic syndromes:
2014 Update on diagnosis, risk-stratification,
and management. Am J Hematol 2014;89(1):97
108.
4. Rollison DE, Howlader N, Smith MT, et al. Epi-
demiology of myelodysplastic syndromes and
chronic myeloproliferative disorders in the
United States, 20012004, using data from the
NAACCR and SEER programs. Blood 2008;
112(1):4552.
5. Goldberg SL, Chen E, Corral M, et al. Incidence
and clinical complications of myelodysplastic
syndromes among United States Medicare bene-
ficiaries. J Clin Oncol 2011;28(17):28472852.
6. Greenberg P, Cox C, LeBeau MM, et al. Interna-
tional scoring system for evaluating prognosis in
myelodysplastic syndromes. Blood 1997;89(6):
20792088.
7. Dayyani F, Conley AP, Strom SS, et al. Cause of
death in patients with lower-risk myelodysplas-
tic syndrome. Cancer 2010;116(9):21742179.
8. Greenberg PL, Tuechler H, Schanz J, et al.
Revised international prognostic scoring system
for myelodysplastic syndromes. Blood 2012;
120(12):24542465.
9. Schanz J, Tuchler H, Sole F, et al. New compre-
hensive cytogenetic scoring system for primary
myelodysplastic syndromes (MDS) and oligo-
blastic acute myeloid leukemia after MDS
derived from an international database merge.
J Clin Oncol 2012;30(8):820829.
10. Greenberg PL, Attar E, Bennett JM, et al. Mye-
lodysplastic syndromes: Clinical practice guide-
lines in oncology. J Natl Compr Canc Netw
2013;11(7):838874.
11. Vardiman JW, Thiele J, Arber DA, et al. The
2008 revision of the WHO classification of mye-
loid neoplasms and acute leukemia: Rationale
and important changes. Blood 2009;114(5):937
951.
12. Haase D, Germing U, Schanz J, et al. New
insights into the prognostic impact of the karyo-
type in MDS and correlation with subtypes: Evi-
dence from a core dataset of 2124 patients.
Blood 2007;110(13):43854395.
13. Jabbour E, Takahashi K, Wang X, et al. Acquisi-
tion of cytogenetic abnormalities in patients
with IPSS defined lower-risk myelodysplastic
syndrome is associated with poor prognosis and
transformation to acute myelogenous leukemia.
Am J Hematol 2013;88(10):831837.
14. Naqvi K, Jabbour E, Bueso-Ramos C, et al.
Implications of discrepancy in morphologic
diagnosis of myelodysplastic syndrome between
referral and tertiary care centers. Blood 2011;
118(17):46904693.
15. Busque L, Patel JP, Figueroa ME, et al. Recur-
rent somatic TET2 mutations in normal elderly
individuals with clonal hematopoiesis. Nat
Genet 2012;44(11):117921181.
16. Jaiswal S, Fontanillas P, Flannick J, et al. Age-
related clonal hematopoiesis associated with
adverse outcomes. N Engl J Med 2014;371(26):
24882498.
hematopoiesis of indeterminate potential and its
distinction from myelodysplastic syndromes.
Blood, in press.
18. DiNardo CD, Daver N, Jain N, et al. Myelodys-
plastic/myeloproliferative neoplasms, unclassifi-
able (MDS/MPN, U): Natural history and
clinical outcome by treatment strategy. Leuke-
mia 2014;28(4):958961.
19. Kantarjian H, OBrien S, Ravandi F, et al. Pro-
posal for a new risk model in myelodysplastic
syndrome that accounts for events not consid-
ered in the original International Prognostic
Scoring System. Cancer 2008;113(6):13511361.
20. Garcia-Manero G, Shan J, Faderl S, et al. A prog-
nostic score for patients with lower risk myelo-
dysplastic syndrome. Leukemia 2008;22(3):538
543.
21. Bejar R, Stevenson KE, Caughey BA, et al. Vali-
dation of a prognostic model and the impact of
mutations in patients with lower-risk myelodys-
plastic syndromes. J Clin Oncol. 2012;30(27):
33763382.
22. Naqvi K, Garcia-Manero G, Sardesai S, et al.
Association of comorbidities with overall sur-
vival in myelodysplastic syndrome: Development
of a prognostic model. J Clin Oncol 2011;
29(16):22402246.
23. Della Porta MG, Malcovati L, Strupp C, et al.
Risk stratification based on both disease status
and extra-hematologic comorbidities in patients
with myelodysplastic syndrome. Haematologica
2011;96(3):441449.
24. Daver N, Naqvi K, Jabbour E, et al. Impact of
comorbidities by ACE-27 in the revised-IPSS for
patients with myelodysplastic syndromes. Am J
Hematol 2014;89(5):509516.
25. Tong WG, Quintas-Cardama A, Kadia T, et al.
Predicting survival of patients with hypocellular
myelodysplastic syndrome: Development of a
disease-specific prognostic score system. Cancer
2012;118(18):44624470.
26. Quintas-Cardama A, Daver N, Kim H, et al. A
prognostic model of therapy-related myelodys-
plastic syndrome for predicting survival and
transformation to acute myeloid leukemia. Clin
Lymphoma Myeloma Leuk 2014;14(5):401410.
27. Bejar R, Levine R, Ebert BL. Unraveling the
molecular pathophysiology of myelodysplastic
syndromes. J Clin Oncol 2011;29(5):504515.
28. Bejar R, Stevenson K, Abdel-Wahab O, et al.
Clinical effect of point mutations in myelodys-
plastic syndromes. N Engl J Med 2011;364(26):
24962506.
29. Papaemmanuil E, Gerstung M, Malcovati L,
et al. Clinical and biological implications of
driver mutations in myelodysplastic syndromes.
Blood 2013;122(22)36163627.
30. Malcovati L, Papaemmanuil E, Bowen DT, et al.
Clinical significance of SF3B1 mutations in mye-
lodysplastic syndromes and myelodysplastic/
myeloproliferative neoplasms. Blood 2011;
118(24):62396246.
31. Papaemmanuil E, Cazzola M, Boultwood J, et al.
Somatic SF3B1 mutation in myelodysplasia with
ring sideroblasts. N Engl J Med 2011;365(15):
13841395.
32. Thol F, Kade S, Schlarmann C, et al. Frequency
and prognostic impact of mutations in SRSF2,
U2AF1, and ZRSR2 in patients with myelodys-
plastic syndromes. Blood 2012;119(15):3578
3584.
33. Haferlach T, Nagata Y, Grossmann V, et al.
Landscape of genetic lesions in 944 patients
with myelodysplastic syndromes. Leukemia
2014;28(2):241247.
34. Itzykson R, Kosmider O, Cluzeau T, et al.
Impact of TET2 mutations on response rate to
azacitidine in myelodysplastic syndromes and
low blast count acute myeloid leukemias. Leuke-
mia. 2011;25(7):11471152.
35. Bejar R, Lord A, Stevenson K, et al. TET2 muta-
tions predict response to hypomethylating
agents in myelodysplastic syndrome patients.
Blood 2014;124(17):27052712.
36. Bejar R, Stevenson KE, Caughey B, et al.
Somatic mutations predict poor outcome in
patients with myelodysplastic syndrome after
hematopoietic stem-cell transplantation. J Clin
Oncol 2014;32(25):26912698.
37. Sekeres MA, Schoonen WM, Kantarjian H, et al.
Characteristics of US patients with myelodys-
plastic syndromes: Results of six cross-sectional
physician surveys. J Natl Cancer Inst 2008;
100(21):15421551.
38. Moyo V, Lefebvre P, Duh MS, et al. Erythropoi-
esis-stimulating agents in the treatment of ane-
mia in myelodysplastic syndromes: A meta-
analysis. Ann Hematol 2008;87(7):527536.
39. Jadersten M, Malcovati L, Dybedal I, et al.
Erythropoietin and granulocyte-colony stimulat-
ing factor treatment associated with improved
survival in myelodysplastic syndrome. J Clin
Oncol 2008;26(21):36073613.
40. Jadersten M, Montgomery SM, Dybedal I, et al.
Long-term outcome of treatment of anemia in
MDS with erythropoietin and G-CSF. Blood
2005;106(3):803811.
41. Park S, Grabar S, Kelaidi C, et al. Predictive fac-
tors of response and survival in myelodysplastic
syndrome treated with erythropoietin and G-
CSF: The GFM experience. Blood 2008;111(2):
574582.
42. Kantarjian HM, Giles FJ, Greenberg PL, et al.
Phase 2 study of romiplostim in patients with
low- or intermediate-risk myelodysplastic syn-
drome receiving azacitidine therapy. Blood 2010;
116(17):31633170.
43. List A, Dewald G, Bennett J, et al. Lenalidomide
in the myelodysplastic syndrome with chromo-
some 5q deletion. N Engl J Med 2006;355(14):
14561465.
44. List A, Kurtin S, Roe DJ, et al. Efficacy of lenali-
domide in myelodysplastic syndromes. N Engl J
Med 2005;352(6):549557.
45. Fenaux P, Giagounidis A, Selleslag D, et al. A
randomized phase 3 study of lenalidomide ver-
sus placebo in RBC transfusion-dependent
patients with low-/intermediate-1-risk myelodys-
plastic syndromes with del5q. Blood 2011;
118(14):37653776.
46. List AF, Bennett JM, Sekeres MA, et al.
Extended survival and reduced risk of AML
progression in erythroid-responsive lenalido-
mide-treated patients with lower-risk del(5q)
MDS. Leukemia. 2014;28(5):10331040.
47. Raza A, Reeves JA, Feldman EJ, et al. Phase 2
study of lenalidomide in transfusion-dependent,
low-risk, and intermediate-1 risk myelodysplas-
tic syndromes with karyotypes other than dele-
tion 5q. Blood 2008;111(1):8693.
48. Fenaux P, Mufti GJ, Hellstrom-Lindberg E,
et al. Efficacy of azacitidine compared with that
of conventional care regimens in the treatment

840 American Journal of Hematology, Vol. 90, No. 9, September 2015 doi:10.1002/ajh.24102
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
of higher-risk myelodysplastic syndromes: A
randomised, open-label, phase III study. Lancet
Oncol 2009;10(3):223232.
49. Kantarjian H, Issa JP, Rosenfeld CS, et al. Deci-
tabine improves patient outcomes in myelodys-
plastic syndromes: Results of a phase III
randomized study. Cancer 2006;106(8):1794
1803.
50. Lyons RM, Cosgriff TM, Modi SS, et al. Hema-
tologic response to three alternative dosing
schedules of azacitidine in patients with myelo-
dysplastic syndromes. J Clin Oncol 2009;27(11):
18501856.
51. Garcia-Manero G, Gore SD, Cogle C, et al.
Phase I study of oral azacitidine in myelodys-
plastic syndromes, chronic myelomonocytic leu-
kemia, and acute myeloid leukemia. J Clin
Oncol 2011;29(18):25212527.
52. Garcia-Manero G, Jabbour E, Borthakur G,
et al. Randomized open-label phase II study of
decitabine in patients with low- or intermediate-
risk myelodysplastic syndromes. J Clin Oncol
2013;31(20):25482553.
53. Young NS, Calado RT, Scheinberg P. Current
concepts in the pathophysiology and treatment
of aplastic anemia. Blood 2006;108(8):2509
2519.
54. Olnes MJ, Sloand EM. Targeting immune dysre-
gulation in myelodysplastic syndromes. JAMA
2011; 305(8):814819.
55. Ganan-Gomez I, Wei Y, Starczynowski DT,
et al. Deregulation of innate immune and
inflammatory signaling in myelodysplastic syn-
dromes. Leukemia, in press.
56. Saunthararajah Y, Nakamura R, Wesley R, et al.
A simple method to predict response to immu-
nosuppressive therapy in patients with myelo-
dysplastic syndrome. Blood 2003;102(8):3025
3027.
57. Sloand EM, Olnes MJ, Shenoy A, et al. Alemtu-
zumab treatment of intermediate-1 myelodys-
plasia patients is associated with sustained
improvement in blood counts and cytogenetic
remissions. J Clin Oncol 2011;28(35):51665173.
58. Zou JX, Rollison DE, Boulware D, et al. Altered
naive and memory CD41 T-cell homeostasis
and immunosenescence characterize younger
patients with myelodysplastic syndrome. Leuke-
mia 2009;23(7):12881296.
59. Kadia TM, Borthakur G, Garcia-Manero G,
et al. Final results of the phase II study of rabbit
anti-thymocyte globulin, ciclosporin, methyl-
prednisone, and granulocyte colony-stimulating
factor in patients with aplastic anaemia and
myelodysplastic syndrome. Br J Haematol 2012;
157(3):312320.
60. Garg R, Faderl S, Garcia-Manero G, et al. Phase
II study of rabbit anti-thymocyte globulin,
cyclosporine and granulocyte colony-stimulating
factor in patients with aplastic anemia and mye-
lodysplastic syndrome. Leukemia 2009;23(7):
12971302.
61. 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(7):
14361441.
62. Passweg JR, Giagounidis AA, Simcock M, et al.
Immunosuppressive therapy for patients with
myelodysplastic syndrome: A prospective
randomized multicenter phase III trial compar-
ing antithymocyte globulin plus cyclosporine
with best supportive careSAKK 33/99. J Clin
Oncol 2011;29(3):303309.
63. Olnes MJ, Scheinberg P, Calvo KR, et al.
Eltrombopag and improved hematopoiesis in
refractory aplastic anemia. N Engl J Med 2012;
367(1):1119.
64. Cutler CS, Lee SJ, Greenberg P, et al. A decision
analysis of allogeneic bone marrow transplanta-
tion for the myelodysplastic syndromes: Delayed
transplantation for low-risk myelodysplasia is
associated with improved outcome. Blood 2004;
104(2):579585.
doi:10.1002/ajh.24102
65. Koreth J, Pidala J, Perez WS, et al. Role of
reduced-intensity conditioning allogeneic hema-
topoietic stem-cell transplantation in older
patients with de novo myelodysplastic syn-
dromes: An international collaborative decision
analysis. J Clin Oncol 2013;31(21):26622670.
66. Takatoku M, Uchiyama T, Okamoto S, et al.
Retrospective nationwide survey of Japanese
patients with transfusion-dependent MDS and
aplastic anemia highlights the negative impact
of iron overload on morbidity/mortality. Eur J
Haematol 2007;78(6):487494.
67. Sanz G, Nomdedeu B, Such E, et al. Independ-
ent Impact of Iron Overload and Transfusion
Dependency on Survival and Leukemic Evolu-
tion in Patients with Myelodysplastic Syndrome.
Blood. 2008;112:640.
68. Greenberg PL, Attar E, Bennett JM, et al. Mye-
lodysplastic syndromes. J Natl Compr Canc
Netw 2011;9(1):3056.
69. Jabbour EJ, Garcia-Manero G, Strati P, et al.
Outcome of patients with low-risk and
intermediate-1-risk myelodysplastic syndrome
after hypomethylating agent failure: A report on
behalf of the MDS Clinical Research Consor-
tium. Cancer 2015;121(6):876882.
70. Attie KM, Allison MJ, McClure T, et al. A phase
1 study of ACE-536, a regulator of erythroid
differentiation, in healthy volunteers. Am J
Hematol 2014;89(7):766770.
71. Suragani RN, Cadena SM, Cawley SM, et al.
Transforming growth factor-beta superfamily
ligand trap ACE-536 corrects anemia by pro-
moting late-stage erythropoiesis. Nat Med 2014;
20(4):408414.
72. Wei Y, Dimicoli S, Bueso-Ramos C, et al. Toll-
like receptor alterations in myelodysplastic syn-
drome. Leukemia 2013;27(9):18321840.
73. Kantarjian H, Oki Y, Garcia-Manero G, et al.
Results of a randomized study of 3 schedules of
low-dose decitabine in higher-risk myelodysplas-
tic syndrome and chronic myelomonocytic leu-
kemia. Blood 2007;109(1):5257.
74. Steensma DP, Baer MR, Slack JL, et al. Multi-
center study of decitabine administered daily for
5 days every 4 weeks to adults with myelodys-
plastic syndromes: The alternative dosing for
outpatient treatment (ADOPT) trial. J Clin
Oncol 2009;27(23)38423848.
75. Lubbert M, Suciu S, Baila L, et al. Low-dose
decitabine versus best supportive care in elderly
patients with intermediate- or high-risk myelo-
dysplastic syndrome (MDS) ineligible for inten-
sive 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(15):1987
1996.
76. Blum W, Garzon R, Klisovic RB, et al. Clinical
response and miR-29b predictive significance in
older AML patients treated with a 10-day sched-
ule of decitabine. Proc Natl Acad Sci U S A.
2010;107(16):74737478.
77. 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(10):24292440.
78. Kornblith AB, Herndon JE II, Silverman LR,
et al. Impact of azacytidine on the quality of life
of patients with myelodysplastic syndrome
treated in a randomized phase III trial: A Can-
cer and Leukemia Group B study. J Clin Oncol
2002;20(10):24412452.
79. Meldi K, Qin T, Buchi F, et al. Specific molecu-
lar signatures predict decitabine response in
chronic myelomonocytic leukemia. J Clin Invest
2015;125(5):18571872.
80. Itzykson R, Kosmider O, Cluzeau T, et al. Pres-
ence of TET2 Mutation predicts a higher
response rate to azacitidine in MDS and AML
post MDS. Blood 2010:abstract 439.
American Journal of Hematology, Vol. 90, No. 9, September 2015
Myelodysplastic Syndromes: 2015 Update
81. Ko M, Huang Y, Jankowska AM, et al. Impaired
hydroxylation of 5-methylcytosine in myeloid
cancers with mutant TET2. Nature
2010;468(7325):839843.
82. Yang H, Fang Z, Wei Y, et al. Levels of miR-
29b do not predict for response in patients with
acute myelogenous leukemia treated with the
combination of 5-azacytidine, valproic acid, and
ATRA. Am J Hematol 2011;86(2):237238.
83. Itzykson R, Thepot S, Quesnel B, et al. Prognos-
tic factors for response and overall survival in
282 patients with higher-risk myelodysplastic
syndromes treated with azacitidine. Blood 2011;
117(2):403411.
84. Wattel E, De Botton S, Luc Lai J, et al. Long-
term follow-up of de novo myelodysplastic syn-
dromes treated with intensive chemotherapy:
Incidence of long-term survivors and outcome
of partial responders. Br J Haematol 1997;98(4):
983991.
85. Beran M, Shen Y, Kantarjian H, et al. High-
dose chemotherapy in high-risk myelodysplastic
syndrome: Covariate-adjusted comparison of
five regimens. Cancer 2001;92(8):19992015.
86. Chang C, Storer BE, Scott BL, et al. Hematopoi-
etic cell transplantation in patients with myelo-
dysplastic syndrome or acute myeloid leukemia
arising from myelodysplastic syndrome: Similar
outcomes in patients with de novo disease and
disease following prior therapy or antecedent
hematologic disorders. Blood 2007;110(4):1379
1387.
87. Van Gelder M, Schetelig J, Volin L, et al. Mono-
somal karyotype predicts poor outcome for
MDS/sAML patients with chromosome 7 abnor-
malities after allogeneic stem cell transplantation
for MDS/sAML. A study of the MDS subcom-
mittee of the Chronic Leukemia Working Party
of the European Group for Blood and Marrow
Transplantation (EBMT). Blood 2009;114:293.
88. de Lima M, Giralt S, Thall PF, et al. Mainte-
nance therapy with low-dose azacitidine after
allogeneic hematopoietic stem cell transplanta-
tion for recurrent acute myelogenous leukemia
or myelodysplastic syndrome: A dose and
schedule finding study. Cancer 2010;116(23):
54205431.
89. Garcia-Manero G, Gore SD. Future directions
for the use of hypomethylating agents. Semin
Hematol 2005;42(3 Suppl 2):S50S59.
90. Sekeres MA, List AF, Cuthbertson D, et al.
Phase I combination trial of lenalidomide and
azacitidine in patients with higher-risk myelo-
dysplastic syndromes. J Clin Oncol 2010;28(13):
22532258.
91. Jabbour E, Garcia-Manero G, Batty N, et al.
Outcome of patients with myelodysplastic syn-
drome after failure of decitabine therapy. Cancer
2010;116(16):38303834.
92. Cabrero M, Jabbour E, Ravandi F, et al. Discon-
tinuation of hypomethylating agent therapy in
patients with myelodysplastic syndromes or
acute myelogenous leukemia in complete remis-
sion or partial response: Retrospective analysis
of survival after long-term follow-up. Leukemia
Res 2015;39(5):520524.
93. Yang H, Bueso-Ramos C, DiNardo C, et al.
Expression of PD-L1, PD-L2, PD-1 and CTLA4
in myelodysplastic syndromes is enhanced by
treatment with hypomethylating agents. Leuke-
mia 2014;28(6):12801288.
94. Takahashi K, Jabbour E, Wang X, et al.
Dynamic acquisition of FLT3 or RAS alterations
drive a subset of patients with lower risk MDS
to secondary AML. Leukemia 2013;27(10):2081
2083.
95. Montalban-Bravo G, Garcia-Manero G. Novel
drugs for older patients with acute myeloid leu-
kemia. Leukemia 2015;29(4):760769.
841