Biol Blood Marrow Transplant 21 (2015) 412e420

Biology of Blood and

Marrow Transplantation
journal homepage: www.bbmt.org

Allogeneic Hematopoietic Cell Transplantation for

Myelodysplastic Syndromes: Lingering Uncertainties and
Emerging Possibilities
Sudipto Mukherjee 1, *, Dominic Boccaccio 2, Mikkael A. Sekeres 1, Edward Copelan 3
1
Leukemia Program, Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
2
Medical Humanities Department, Davidson College, Davidson, North Carolina
3
Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina

Article history: a b s t r a c t
Received 5 February 2014 The landscape of transplantation in myelodysplastic syndrome (MDS) has evolved rapidly in the last decade,
Accepted 25 July 2014 driven mostly by advances in patient selection through better risk stratification, increasing age of allogeneic
recipients, introduction of reduced-intensity conditioning regimens, increased availability of unrelated do-
Key Words: nors, new donor sources, and improvements in transplant technology and supportive care. Despite these
MDS advances, several issues, mostly centering on approaches to improve post-transplant survival while mini-
HCT mizing transplant-related mortality, continue to present significant challenges. Advances in understanding
Mutations
the molecular pathogenesis of MDS have made it feasible to construct clinically useful risk models that
Donor
integrate prognostic genes with conventional risk parameters for better selection of patients likely to benefit
Relapse
from hematopoietic cell transplantation. Simultaneous research efforts in several areas, including comor-
bidity assessment, novel preparative regimens, optimal pretransplant cytoreductive strategy, and post-
transplantation therapies, are expected to improve long-term disease-free survival and quality of life.
Ó 2015 American Society for Blood and Marrow Transplantation.

INTRODUCTION of pretransplant cytoreductive therapy, and the optimal

Myelodysplastic syndromes (MDS) is a heterogeneous
collection of clonal hematopoietic stem cell disorders char-
acterized by ineffective hematopoiesis leading to peripheral
cytopenias and related complications and a variable risk of
progression to acute myeloid leukemia (AML). According to
Surveillance Epidemiology and End Results, MDS is the most
common myeloid malignancy in the United States, with most
patients (88%) older than 60 years at diagnosis [1]. Allogeneic
hematopoietic cell transplantation (HCT) is the only known
treatment modality with curative potential in MDS. Although
HCT outcomes in MDS have improved over the last decade,
several challenges pertaining to transplant-related mortality
(TRM) and morbidity remain. This review summarizes the
advances made in the last decade, focusing mainly on more
nuanced disease risk stratification, transplant implications of
newly identified molecular mutations, the emerging role of
haploidentical and umbilical cord blood (UCB) grafts, the role
Financial disclosure: See Acknowledgments on page 418.
* Correspondence and reprint requests: Sudipto Mukherjee, MD, PhD,
MPH, Associate Staff, Leukemia Program, Department of Hematologic
Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute,
R35, 9500 Euclid Avenue, Cleveland, OH 44195.
E-mail address: mukhers2@ccf.org (S. Mukherjee).
timing of transplantation.
EPIDEMIOLOGY OF TRANSPLANTATION IN MDS: A TALE
OF UNMET NEEDS
Over the last decade, the number of transplants per-
formed for MDS has risen dramatically, particularly in older
adults, mainly because of increasing numbers of unrelated
donor (URD) and reduced-intensity conditioning (RIC)
transplants (Figure 1) [2]. This has been accompanied by
significant decreases in overall mortality (by 40%) and im-
proved long-term survival because of decreased transplant-
related complications, notably infections, organ toxicities,
and severe acute graft-versus-host disease (GVHD) [3]. These
results are even more promising considering that trans-
planted cohorts in recent years are on average older by
2 decades compared with their counterparts from the late
1980s and the proportion of URD recipients increased from
6% to 57% in the same interval (exceeding related donors) [4].
The Center for International Blood and Marrow Trans-
plant Research (CIBMTR) reports MDS as the third most
common indication for allogeneic HCT, with 1016 transplants
registered between 2008 and 2010 [2]. A comparable trend
has been reported in Europe, where the European Group for
Blood and Marrow Transplantation (EBMT) registered a

http://dx.doi.org/10.1016/j.bbmt.2014.07.027
1083-8791/Ó 2015 American Society for Blood and Marrow Transplantation.
 S. Mukherjee et al. / Biol Blood Marrow Transplant 21 (2015) 412e420 413

Figure 1. Number of allogeneic HCTs for MDS patients
65 years of age in the
United States, 2005-2012. Data compiled by CIBMTR. Figure provided by Dr.
Mary Horowitz and adapted with permission.
doubling in the number of allogeneic HCT for MDS/second-
ary AML (sAML) from 737 to 1636 between the years 2001
and 2010, paralleled by a 10% to 33% increase in HCT use in
patients over age 60 [5]. Although these temporal trends are
impressive, when considered in the context of the entire pool
of high-risk MDS patients in the United States, statistics from
various epidemiologic sources suggest a staggeringly low use
of transplantation in this population, as shown in Figure 2
[6-10]. A prospective feasibility study of RIC HCT in 259
higher risk MDS/AML patients reported that only 14 patients
(5%) harboring unfavorable cytogenetics eventually received
transplantation [11]. The findings of a cross-sectional survey
of US physicians from different geographic regions and a
wide variety of practice settings are even more sobering,
with only 4% of recently diagnosed MDS patients referred for
HCT [8]. With 21 million potential marrow donors world-
wide, including more than 600,000 UCB units, it is expected
that a suitable URD or UCB unit can be found to meet the
needs of approximately 12,000 patients in the United States
who need URD transplantations every year. Despite this and
results comparable with those with HLA-identical sibling
donors, the estimated usage of these donor sources is strik-
ingly low, at 10% for 65- to 74-year-olds, the demographic
cohort with the highest MDS rates [10]. Figures from 2012
show that a formal search was initiated for only 62% of these
patients of which only 60% actually proceeded to HCT [12].
Although the reasons for low utilization of HCT are
multifactorial, most of the concerns center around the high
risk of TRM or diminution of quality of life due to chronic
GVHD or other delayed effects of HCT, especially so in older
patients with diminished physiologic reserves because of the
combined effect of their advanced age and existing comor-
bidities. Limited understanding of referring physicians re-
garding transplant eligibility, late transplant referrals, delay
in HLA typing, and underuse of URD transplantation is also
responsible. The feasibility of surmounting some of these
barriers was demonstrated in a recent study in which a
combination of pragmatic strategies, including use of alter-
native donors, different graft sources, and RIC regimens
(42%), allowed 67% of AML patients in complete remission to
proceed to HCT [13]. A concerted effort in educating the
clinicians providing care for MDS patients would result in
more frequent and earlier consideration of this modality.
WHO NEEDS A TRANSPLANT? SEPARATING THE GOOD
FROM THE BAD AND THE UGLY
Selection of the appropriate transplant candidate has
undergone refinements over the past decade, aided by
improved understanding of disease risk, use of disease-
modifying therapies that improve survival (since 2004),
more sensitive tools to assess transplant vulnerability, and
increased HCT opportunities in the elderly with the advent of
RIC and nonmyeloablative (NMA) regimens. As shown in
Table 1, upfront HCT is currently recommended for fit MDS
patients stratified as higher risk based on clonal chromo-
somal abnormalities, blast percentage, peripheral cytope-
nias, and additional features depending on the particular
prognostic model applied. Originally designed to prognosti-
cate for nontransplanted patients, several risk models, such
as the International Prognostic Scoring System (IPSS), the
World Health Organization classification-based Prognostic
Scoring System (WPSS), and the revised IPSS (IPSS-R), also
predict survival and relapse in the transplant setting
[4,14,15], even in those receiving RIC [14,15]. The newly

Figure 2. Crude estimation of transplant-eligible older MDS patients (age >60-65 years) in the United States with data extrapolated from contemporaneous pop-
ulation registries highlighting the staggeringly low uptake of allogeneic HCTs in this age group. SEER indicates Surveillance Epidemiology and End Results; NAACCR,
North American Association of Central Cancer Registries; NHANES III, National Health and Nutrition Examination Survey III; alloHSCT, allogeneic hematopoietic stem
cell transplantation. * MDS cases equal to or greater than 60 years were extracted from all 18 SEER registries using the R package SEERaBomb available at http://
cran.r-project.org/web/packages/SEERaBomb/index.html (courtesy of Dr. Tomas Radivoyevitch).
414 S. Mukherjee et al. / Biol Blood Marrow Transplant 21 (2015) 412e420
Table 1
Indications for Transplantation in MDS Based on Different Risk Assessments
Definite Prognostic modelebased risk score
IPSS intermediate-2
IPSS high
IPSS-R high risk
IPSS-R very high risk
WPSS high risk
WPSS very high risk
Disease morphology
RAEB-1, RAEB-2
RAEB-t
Probable Presence of poor prognostic features (clinical and/or
pathologic)
Failure of HMA
Transfusion dependency despite growth factor support
Severe neutropenia/thrombocytopenia (even with low
IPSS scores)
High-risk cytogenetic abnormalities (IPSS-R)*
Secondary/therapy-related MDS
IPSS indicates International Prognostic Scoring System; WPSS, the World
Health Organization classification-based Prognostic Scoring System; IPSS-R,
revised IPSS; RAEB-1, refractory anemia with excess blasts-1; RAEB-2, re-
fractory anemia with excess blasts-2; RAEB-t, refractory anemia with excess
blasts in transformation.
* inv(3)/t(3q)/del(3q), 7; double abnormalities including 7/del(7q),
and complex (
3 abnormalities).
proposed 5-group cytogenetic risk classification has greater
discriminatory capacity in predicting post-HCT relapse and
mortality than the 3 IPSS risk categories and reassigns risk of
65% of “classic” IPSS patients [4]. Applying the 5-group
criteria, the IPSS poor-risk cytogenetics group can be strati-
fied into 3 additional risk groups, intermediate, poor, and
very poor, with high relapse rates of 30% and 50% for the
latter two cohorts.
In a large series of 519 patients transplanted for MDS or
oligoblastic AML (<30% marrow blasts), Gruppo Italiano
Trapianto di Midollo Osseo (GITMO) confirmed the high-risk
IPSS-R category as an independent predictor of relapse and
lower survival [15]. Additionally, the presence of monosomal
karyotype, particularly those with chromosome 7 abnor-
mality (even when present as an isolated abnormality),
significantly worsens prognosis beyond that of a complex
karyotype [4,16]. In one series, no patient with the mono-
somal karyotype was alive at 5 years post-transplant
compared with the 5-year overall survival (OS) rate of 37%
in those without the monosomal karyotype [16]. These data
suggest that standard HCT approaches may be futile in some
high-risk patients, and clinical trials might be a more rational
approach. Emerging data support early HCT in certain sub-
sets of lower risk IPSS patients who exhibit an aggressive
clinical course characterized by severe thrombocytopenia,
transfusion dependency, or marrow fibrosis [17].
DEFINING RISK BEYOND CYTOGENETICS: WAR OF THE
CLONES
High-throughput sequencing analysis has revealed the
complex genomic landscape of MDS with identification of
recurrent somatic mutations in over 40 genes involved in
several pathways, including signal transduction, epigenetic
regulation, transcriptional regulation, and RNA splicing,
among others. These somatic mutations are highly prevalent,
affecting a staggering 90% of MDS patients, including 50% to
70% of patients with normal cytogenetics [18,19]. Several
of these mutations have been shown to independently influ-
ence survival in nontransplant setting [18-21] and can upstage
IPSS or IPSS-R predicted disease risk. For patients harboring
mutations in any of the 5 genes TP53, EZH2, ETV6, RUNX1, and
ASXL1, the median survival was significantly shorter than
predicted by IPSS and resembled that of the next highest IPSS
risk group [19]. In lower risk MDS patients (low and inter-
mediate risk-1 [IR-1] IPSS risk), presence of EZH2, RUNX1, and
ASXL1 independently predicted for higher risk of death
compared with unmutated counterparts even after adjusting
for IPSS [20]. In addition, an increasing number of oncogenic
driver mutations in an individual patient also predicted for
deterioration in leukemia-free survival [21]. None of the risk
models in clinical use has yet incorporated these mutations in
their prognostic algorithm, resulting in the likelihood of a
substantial number of high-risk patients being treated
less aggressively because of inaccurate risk assignment.
Mutation-based models based solely on molecular markers
can identify prognostic risk groups with different survival
probabilities [18,21], and when combined with IPSS-variables
have been shown to enhance prognostication [18-21].
The impact of these mutations on post-transplant out-
come in MDS patients was investigated by Thol et al. [22],
who analyzed the impact of the 3 most commonly mutated
spliceosomal genes, U2AF1, SRSF2, and SF3B1, in 339 patients
transplanted for MDS/sAML. Only U2AF1 mutations inde-
pendently predicted for shorter OS (P ¼ .011) and higher cu-
mulative incidence of relapse (P ¼ .007). Hamilton et al. [23]
reported a survival advantage in patients with U2AF1 or
SRSF2 mutations who underwent upfront HCT compared with
those who received high-intensity chemotherapy or hypo-
methylating agents (HMAs) (53 versus 17 months, P ¼ .05). No
difference in OS, relapse, and nonrelapse mortality (NRM)
was reported between wild-type and mutated SRSF2 patients,
suggesting HCT can abrogate the adverse effects of SRSF2 [24].
Mutations in TP53, TET2, and DNMT3A have been signifi-
cantly associated with shortened survival following HCT after
adjusting for known adverse disease and transplant-related
predictive variables (Dr. Rafael Bejar, personal communica-
tion). Patients with TP53 mutations in particular had worst
outcomes, with a median post-transplant survival of only
4.6 months, raising questions about any benefit of HCT in this
group. As shown in Figure 3, several mutations predict for
poor survival in a population of lower risk patients, and such
patients should be treated as high risk and considered for
early HCT, preferably in the context of clinical trials because
prospective data are lacking.
DO ALL THERAPY-RELATED MDS/AML PATIENTS NEED
TRANSPLANTATION? NOT ALL CURES ARE POISON
Another question that has garnered increasing attention
is whether HCT should be recommended for all therapy-
related MDS/AML (t-MDS/AML) patients. With overre-
presentation of poor-risk cytogenetic features including,
chromosome 5 and/or 7 abnormalities in 70% of t-MDS/AML
patients and median survival of 6 to 8 months, trans-
plantation alone has been thought to offer long-term dis-
ease-free survival. However, this concept is challenged by
data that suggest the biology and outcome of t-MDS/AML
depends on the treatment modality originally received. The
outcomes of transplanted t-MDS/AML patients reported to
CIBMTR and EBMT is reflective of exposure to chemotherapy
or combined modality, considering 82% and 95% of the entire
cohort in the registries, respectively, had such an exposure
[25,26]. Nardi et al. [27] reported that MDS developing after
radiation monotherapy behaves like de novo disease, with no
significant differences in median survival (38 versus 30
months) and a similar prevalence of chromosome 5 and 7
abnormalities in both groups [27]. When compared with
 S. Mukherjee et al. / Biol Blood Marrow Transplant 21 (2015) 412e420
Figure 3. (A) Comparison of median survival of MDS patients stratified by
IPSS-R cytogenetic risk categories or based on presence of prognostic molec-
ular mutations. Median survival predicted by the molecular mutations as
shown in the figure were adjusted for the IPSS risk group assigned at the time
of sample collection. IPSS-R Int, Poor and Very Poor indicate intermediate,
poor, and very poor cytogenetic categories in revised International Prognostic
Scoring System (IPSS-R). (B) Comparison of overall survival in patients with
any of the prognostically adverse somatic mutations (in TP53, EZH2, RUNX1,
ASXL1, or ETV6) to unmutated patients within each of the IPSS-R “lower” risk
groups identifies added disease risk in each of the categories. Dotted arrows
indicate decrease in survival in the presence of any of the 5 mutations. (Mo-
lecular data provided by Dr. Rafael Bejar and adapted with permission. Figures
courtesy of Dr. Aaron Gerds.)
patients treated with chemotherapy alone or in combination
with radiation, those who developed MDS after definitive
radiotherapy had better OS rates and a lower incidence of
high-risk karyotypes. New data also raise question about
whether all radiation-related MDS cases are truly t-MDS. A
retrospective study of 11,000 prostate cancer patients
showed no excess risk of MDS in those who underwent
radiation monotherapy (n ¼ 5119) compared with those
treated with radical prostatectomy (the control group) and
with population-based registries [28]. Analogous to findings
from the t-AML literature [29] and taking into account the
fact that these patients may have transplant vulnerabilities
from cumulative toxicities of prior therapies, it might be
reasonable to treat radiation-related MDS, and perhaps other
t-MDS patients, without high-risk cytogenetic features like
de novo lower-risk disease using nontransplant approaches.
IMPACT OF RECIPIENT AGE: BIOLOGY TRUMPS
CHRONOLOGY
Although there is broad consensus for recommending
HCT for appropriate higher-risk younger MDS patients,
415
considerable controversy exists in older adults. The identi-
fication of a patient as “elderly” in the transplantation liter-
ature varies by study, with most referring to patients aged 50
to 70 years. With advancing patient age, increased rates of
TRM, particularly with myeloablative (MA) conditioning
regimens, have been observed [30]. However, an accumu-
lating body of evidence shows that HCT can be performed
safely in older individuals selected based on limited
comorbidities.
McClune et al. [31] analyzed 1080 patients with MDS
(n ¼ 535) or AML in first complete remission (n ¼ 545),
identified from the CIBMTR, who underwent RIC or NMA
conditioning followed by HCT between 1995 and 2005. No
significant difference in 2-year risk of NRM, relapse, disease-
free survival, OS, or GVHD was observed across 4 age cohorts:
40 to 54 years, 55 to 59 years, 60 to 65 years, and >65 years.
Lim et al. [32] performed a similar analysis of a contempo-
raneous cohort of 1333 MDS patients registered in the EBMT
who received MA (n ¼ 500) or RIC (n ¼ 833) transplantation
between 1998 and 2006. When compared with the 50- to 59-
year age group, patients >60 years had comparable NRM
(36% versus 39%), relapse (32% versus 41%), and OS (34%
versus 27%) at 4 years. Although advanced disease stage at
the time of transplantation was the most important prog-
nostic variable for OS in the EBMT series, in the CIBMTR study
performance status, HLA disparity, and unfavorable cytoge-
netics predicted for poor OS and disease-free survival. Of
note, only 34% and 10% of transplanted MDS patients in the
CIBMTR and EBMT series, respectively, were over age
60 years, likely identifying a selection bias. Two studies in
septuagenarians with MDS observed no increase in adverse
transplant-related outcomes [30,33]. Although chronologic
age should not be an exclusion criterion for transplantation,
it must be considered in decision making because of the
increased prevalence of comorbidities and age-related
decline in organ function.
IMPACT OF COMORBIDITIES: FULFILLING THE
DARWINIAN RULE (THE FITTER, THE BETTER)
Several pretransplant scoring systems objectively char-
acterize transplant vulnerability and predict outcomes. The
most widely accepted is the HCT Comorbidity Index (HCT-CI),
which reliably predicts toxicities, NRM, and OS in MDS or
AML patients receiving MA or RIC transplants [34]. An HCT-CI
composite score >3 predicted for an exceedingly high 2-year
NRM (hazard ratio, 5.35) and inferior 2-year OS (hazard ratio,
5.27). To further refine risk prediction, Sorror et al. [35]
proposed a modified HCT-CI that integrated the classic
HCT-CI scores with disease risk determined by morphology,
remission status, and cytogenetics. Low disease risk, mostly
refractory anemia and refractory anemia with ring side-
roblasts with an HCT-CI of 0 to 2, predicted for best outcome,
with a low NRM of 4% and 11% and a high 2-year OS of 70%
and 78% after NMA and MA conditioning, respectively. Those
with intermediate-/high-risk disease and HCT-CI >3 fared
worst, with NRM of 29% and 46% after NMA and MA condi-
tioning, respectively and corresponding OS of 29% and 24%,
respectively.
Impaired functional status, as measured by the Karnofsky
performance scale (KPS) or the Eastern Cooperative Oncology
Group scale, independently predicts for worse transplant
outcome. Typically, published studies have used KPS score
<70% or Eastern Cooperative Oncology Group score of 2 or
less as exclusion criteria for transplantation. However, these
“cutoff” criteria may not entirely capture transplant
416 S. Mukherjee et al. / Biol Blood Marrow Transplant 21 (2015) 412e420
vulnerability, as shown in the CIBMTR registry where 16% of
patients 65 years or older fared poorly despite KPS score
>70%. To better characterize transplant risk beyond HCT-CI
and performance scales, Muffly et al. recently proposed use
of a comprehensive geriatric assessment tool that uncovered
a high prevalence of impairments in functional status, frailty,
disability, and mental health in HCT recipients >50 years old
who were assessed as fit by standard risk criteria [36].
The negative impact of iron overload on transplant
outcome in transfusion-dependent MDS patients has been a
subject of ongoing debate. In contrast to retrospective ana-
lyses that evaluated HCT outcomes based on serum ferritin
levels, a recent prospective study used pretransplant mag-
netic resonance imagingequantified hepatic iron concen-
tration as a marker of hyperferritinemia and reported no
effect on OS or NRM [37]. Whether pretransplant iron che-
lation can improve transplant outcomes has never been
prospectively studied.
TIMING OF TRANSPLANTATION: BRINGING OUT THE
BIG GUNS
Although early HCT is indicated in patients with higher-
risk MDS provided the recipient is fit and a donor available,
the optimal timing of transplantation remains a clinical
challenge in many MDS patients, especially with the intro-
duction of HMAs that improve survival and the availability of
clinical trials. Although not routinely recommended, there is
evidence of high success rates with modest toxicity when
HCT is performed in early-stage disease or low-risk IPSS
categories [38,39]. Analysis of EBMT registry data showed an
absolute increase in OS of 10% at 4 years in patients with re-
fractory anemia and refractory anemia with ring sideroblasts
who underwent earlier transplantation (<12 months) from
the time of diagnosis, mainly because of lower NRM [38].
Similar outcomes were reported by Deeg et al. [39] in their
cohort of IPSS low-risk patients with no reported relapses and
80% relapse-free survival compared with corresponding fig-
ures of 42% and 29% observed in the high-risk group. These
single-arm studies are inherently limited by selection bias,
and in the absence of any prospective data comparing HCT
with nontransplantation approaches, it remains unclear
whether transplantation early in disease course confers any
survival advantage. GITMO experience indicates optimal
benefit of HCT when performed before progression of disease
to an advanced stage [14].
Results of a Markov decision analysis showed a beneficial
role of early HCT in younger patients with IR-2 or high-risk
IPSS disease undergoing MA transplantation with HLA-
identical sibling grafts, whereas delaying transplant until
leukemic evolution led to longer life expectancy in patients
with low and IR-1 disease [40]. However, the study findings
are not applicable to most MDS patients typically seen in
daily clinical practice because the data pertain to an exclu-
sively young cohort (<60 years) and predated the era of
HMAs. To address these limitations, Koreth et al. [41] used a
similar statistical approach to compare the outcome of 2
different treatment arms, RIC HCT and nontransplantation
strategies (best supportive care, hematopoietic growth fac-
tors, and HMAs), in patients >60 years. This analysis similarly
showed best survival with nontransplantation strategies in
older patients with lower-risk MDS with near doubling of
median life expectancy compared with HCT (77 versus
38 month). For higher-risk disease, only a modest survival
advantage was seen with earlier transplant compared with
HMAs (36 versus 28 months) with this benefit apparent only
after 40 months of follow-up.
Two contemporaneous European registry analyses, how-
ever, showed differing results [42,43]. The GITMO-Pavia
study adopted a continuous-time multistate Markov model
using IPSS and WPSS risk categories as time-dependent in-
dicators of the natural course of MDS to estimate and
compare life expectancy from diagnosis [42]. This analysis
failed to show any survival advantage by delaying transplant
in the IR-1 group, a significant finding considering that almost
50% of the patients in the Cutler study [40] had IR-1 disease.
Based on the best WPSS-based transplantation strategy in
this model, lower-risk IPSS patients with multilineage
dysplasia and/or transfusion dependency benefit from early
HCT, whereas outcomes are better if transplant is delayed for
IR-1 patients who have favorable cytogenetics or those
without excess blasts. A recent EBMT study used several
statistical models to compare treatment outcomes of older
MDS patients (>55 years) with refractory anemia with excess
blasts or refractory anemia with excess blasts in trans-
formation who underwent transplantation (EBMT registry) or
were managed with nontransplant strategies (Düsseldorf
Registry) and reported no survival advantage with HCT [43].
Notably, this study exposed the limitation of drawing con-
clusions about the causal effect of time interval from diag-
nosis to transplant on outcome using observational data, even
with the most sophisticated mathematical models.
The unavoidable flaw in these models is the reliance on
crucial assumptions that do not reflect nonproportional dis-
tribution of hazards (related to patient and disease-risk pa-
rameters) among the comparator groups. The question of
whether there is any survival advantage with transplant in
older adults is being addressed prospectively by a phase III
trial (BMT CTN 1102) that will biologically assign patients aged
50 to 75 years with IPSS IR-2 and high-risk disease to RIC HCT
or non-HCT treatment (HMAs or best supportive care) based
on availability of suitable matched related donor or URD.
Transplant decisions present additional challenges in
patients on HMA therapy. Clinical responses to HMA are seen
after 4 to 6 months of therapy, and of the roughly 50% of
patients who respond, the median duration of response is
only 9 to 15 months, with most losing response within 1 to
2 years [44,45]. In those who fail azacitidine, the median
survival is dismal at <6 months [46]. This raises several
questions. Is it possible to identify patients who have a low
probability of responding to HMAs and consider them for
upfront HCT or other alternative approach? In those who are
responders, should HMAs be continued until disease pro-
gression or should they be transplanted while they are in
remission?
Based on recent evidence, patients harboring TET2 and or
DNMT3A mutations are more likely to respond to HMAs, but
this has not been validated prospectively [47,48]. Deferring
transplant until the time of disease progression can jeopar-
dize HCT chances because of several factors, notably un-
controlled disease, acquisition of highly resistant clonal
abnormalities and comorbidities, or treatment-related tox-
icities accumulated over the course of disease. Long-term
disease-free survival (median of 19.5 months) with HCT can
be achieved in only a small subset of patients who fail HMA
[46]. Among the azacitidine-treated cohort, a nonsignificant
improvement in median survival was seen in those who had
stable disease at the time of azacitidine discontinuation
compared with those who underwent transplantation with
progressive disease (not reached versus 17 months) [46].
 S. Mukherjee et al. / Biol Blood Marrow Transplant 21 (2015) 412e420
Thus, consultation to discuss HCT should be routinely offered
to higher-risk patients who are transplant eligible shortly
after diagnosis. Early transplantation without exposure to
pretransplant agents in patients with higher-risk disease
who are willing and able is reasonable.
DONOR SELECTION: SOMETHING FOR MISMATCHED,
UNRELATED, AND HAVE NOTS
With high-resolution HLA typing, outcomes of 8/8
matched URD recipients are comparable with HLA-identical
siblings, with the exception of slightly higher rates of acute
and chronic GVHD [49]. The question of whether a younger
matched unrelated donor (MUD) rather than an older MSD
improves outcome was addressed in an EBMT series of 719
MDS patients (>50 years), showing a significant survival
advantage with allografts originating from younger MUDs
(<30 years) compared with older MUDs or MSDs [50]. In
contrast, CIBMTR analysis reported better outcomes with
older matched related donor (>50 years) than young URD
(<50 years), particularly in recipients with poor pretrans-
plant performance scores [51]. The preferential source of
hematopoietic progenitor cells for URD transplantation was
addressed in an international randomized trial that demon-
strated comparable survival rates but a higher incidence of
chronic GVHD with peripheral blood stem cells compared
with bone marrow grafts [52]. We favor the use of sibling
donors with peripheral blood stem cells because of earlier
engraftment and better quality of life.
In the absence of a suitable MSD or URD, unrelated UCB
cells or cells from HLA-haploidentical family donors provide
reasonable alternatives. Majhail et al. [53] assessed the
feasibility of UCB transplants in 98 older MDS/AML patients
(>55 years) by prospectively comparing outcomes between
4-6/6 HLA-matched UCB and MSD after RIC HCT and reported
no significant difference in 3-year OS (37% versus 31%),
relapse, or TRM. In single UCB transplantation, higher cell
doses predict for improved survival [54], and in cases of low
cell doses, alternative approaches include infusion of double
cord blood units or a single cord blood unit after in vitro
expansion [55,56]. Outcomes similar to matched related
donor and MUD recipients have been reported with hap-
loidentical transplants using T cellereplete grafts and high-
dose post-transplantation cyclophosphamide after NMA
conditioning [57]. The low incidence of chronic GVHD after
post-transplant cyclophosphamide is a particular advantage
of this approach.
PRETRANSPLANT CYTOREDUCTION: TAMING THE ROGUE
MARROW
Pretransplant blast burden (>5% marrow blasts) and
failure to achieve complete remission significantly correlate
with relapse in MDS patients undergoing HCT, particularly
with RIC regimens [58,59]. Retrospective studies examining
the role of induction chemotherapy before HCT showed no
convincing benefit [60]. Use of HMAs as a bridging therapy to
HCT offers an alternative to induction chemotherapy to
reduce blast burden with fewer treatment-related toxicities.
The French Society of Bone Marrow Transplantation and Cell
Therapy conducted the largest study on the use of azacitidine
before HCT and reported no significant differences in out-
comes among patients who received azacitidine or induction
chemotherapy before transplantation [61]. It also found that
patients who required both azacitidine and induction
chemotherapy had poorer outcomes. Oran et al. [62] found
no difference in event-free survival among high-risk MDS
417
patients who underwent transplantation after chemo-
therapy alone, HMAs, both, or no prior therapy. Jabbour et al.
[63] did not observe any benefit of HCT after HMA therapy
compared with upfront HCT. Gerds et al. presented data on
68 MDS and sAML patients pretreated with AZA (n ¼ 35) or
IC (n ¼ 33) prior to allo-HSCT and similarly reported no dif-
ference in 1 year survival, NRM and relapse between the
groups [64]. The failure to demonstrate a benefit for therapy
before transplantation suggests that high-risk MDS patients
should, where possible, proceed directly to transplant
without delay [62]. Because rates of complete remission are
higher with induction chemotherapy than with HMA, this
should be considered as an option to rescue younger fit pa-
tients with high disease burden. However, for those with
poor-risk cytogenetic abnormalities, evidence suggests use
of HMAs over induction chemotherapy is reasonable. In older
individuals with comorbidities awaiting RIC HCT, use of
HMAs as “bridging therapy” to prevent disease progression is
an acceptable approach.
PREPARATIVE REGIMENS: HOW MUCH MARROW
ABLATION IS ENOUGH?
Few studies confined to MDS patients have directly
compared the effectiveness and toxicity of specific condi-
tioning regimens. Traditionally, MA preparation using total
body irradiation (TBI)- or busulfan-based regimens have
been used. Of adults with MDS who underwent HCT from
HLA-MSD or adult URD in the United States between 2002
and 2006 reported from the CIBMTR, nearly 60% received MA
regimens [49]. RIC, however, has been increasingly used over
the last few years.
Although TBI-based MA regimens are effective and were
predominantly used for patients with MDS until the last
decade [58,65], the use of busulfan-based regimens has
progressively increased [39,66]. Advances in busulfan
administration, including i.v. administration [67] and/or
targeted plasma levels based on pharmacokinetics, have
improved results [39]. Deeg et al. [39] combined oral
busulfan targeted to predetermined plasma levels in com-
bination with cyclophosphamide in 109 patients with MDS
receiving hematopoietic cells from related or unrelated do-
nors. NRM at 100 days and 3 years were 12% and 28% for
related and 13% and 30% for unrelated recipients. Relapse-
free survival at 3 years was 56% and 59%, respectively, and
this regimen appeared to be better tolerated and safer than
traditional TBI regimens, including in patients older than
60 years of age [39].
Intravenous administration of busulfan is associated with
decreased incidences of hepatic veno-occlusive disease and
early mortality [67]. A recently reported large retrospective
analysis from the CIBMTR of AML patients in first remission
who underwent transplantation between 2000 and 2006
demonstrated significantly lower NRM, relapse-free survival,
and OS rates using i.v. busulfan (1-year NRM of 12%)
compared with TBI in combination with cyclophosphamide
[68]. A subsequent cohort of patients undergoing trans-
plantation between 2008 and 2011, including patients with
MDS, also showed better survival in patients receiving i.v.
busulfan compared with TBI [69]. An MA regimen of busulfan
combined with fludarabine has gained popularity because
of reported decreased toxicity compared with busulfane
cyclophosphamide; however, a randomized study in AML
indicated higher relapse rates and lower survival compared
with busulfanecyclophosphamide [70].
418 S. Mukherjee et al. / Biol Blood Marrow Transplant 21 (2015) 412e420
RIC regimens have extended the use of allogeneic
transplantation to selected older patients and those with
comorbidities that place them at high risk of TRM with
MA preparation. For patients with MDS, lower intensity
conditioning is associated with higher risk of relapse [71-
73], lower NRM, and generally similar survival to MA
regimens [73]. Nonablative regimens, however, have been
associated with substantially higher relapse rates and
lower relapse-free survival and OS than MA conditioning
[5,75]. RIC regimens generally including lower than MA
doses of busulfan or melphalan combined with fludar-
abine can cure a significant proportion of patients with
MDS who would be at high risk of mortality with MA
therapy. Other regimens, including 550-cGy TBI with
cyclophosphamide, have also proven to be well tolerated
and effective [74].
A retrospective study from the EBMT reported that 38%
of patients older than 50 years with MDS received an MA
regimen [32]. No difference in NRM or survival was
detected in this analysis among patients <60 years of age
compared with those
60 years. Because relapse remains a
particular concern in patients with
5% marrow blasts,
adverse cytogenetics, or molecular mutations, MA therapy
may be appropriate in selected patients up to at least
70 years of age [5,71]. At present, we favor the use of MA
i.v. busulfan-based regimens in patients without significant
comorbidities and RIC regimens in those with significant
comorbidities, particularly when accompanied by lower-
risk MDS. Well-designed prospective studies to analyze
the relative effectiveness and toxicity of specific MA and
RIC regimens in patients at varied risk of relapse and TRM
are needed. Two randomized trials were designed to pro-
spectively compare toxicity and efficacy between patients
receiving high-intensity and reduced-intensity regimens:
EBMT NCT00682396 and BMT CTN 0901 NCT01339910.
Preliminary review suggesting a benefit of the MA arm
over RIC regimens led to the early closure of the BMT CTN
0901 trial.
POST-TRANSPLANTATION RELAPSE
After relapse prognosis is extremely poor, especially if
relapse occurred within a year of HCT. In the absence of any
randomized trials, there is no clear consensus about post-
transplant treatment strategies. Several efforts to reduce
relapse rates after transplantation include withdrawal of
immunosuppression, HMAs [76,77], infusion of selected
populations of donor lymphocytes [78], and, occasionally, a
second HCT. It is postulated that azacitidine can enhance the
graft-versus-leukemia effect by increased expression of
cancer-testis antigens [79] that become potential targets for
the donor immune system and hence can play a role in dis-
ease control after transplant. The role of azacitidine for
treating relapse was studied by de Lima et al. [77] in a phase I
dose escalating trial. Monthly doses of 32 mg/m2 daily for
5 days beginning 40 days after HCT resulted in 1-year OS and
event-free survival rates of 77% and 58%, respectively.
Azacitidine has also shown some activity when used in
combination with donor lymphocyte infusions in relapsed
AML/MDS patients [80]. As maintenance therapy after
transplantation, azacitidine appears to be well tolerated with
no impact on GVHD.
An ongoing randomized trial (NCT00887068) is com-
paring azacitidine versus current standard of care after
allogeneic HCT. Lenalidomide has been tried as maintenance
therapy in del(5q) MDS/AML but results in increased rates of
GVHD [81]. Treatment decision based on detection of mini-
mal residual disease after transplantation is a growing area
of research. Platzbecker et al. [76] reported monitoring
recipient CD34þ lineage-specific chimerism as a marker of
minimal residual disease to preemptively start treatment
with azacitidine [76]. With the discovery of prognostic
molecular markers in MDS, it is expected that these will
increasingly become an integral part of minimal residual
diseaseebased treatment strategies.
CONCLUSION
Although the use of HCT in MDS has become safer
and more widespread, it remains underused. Clinicians
should be cognizant of the newly identified molecular
mutations that can help identify patients who would
benefit from transplantation but who are outside the
paradigm of current decision models. Future efforts to
improve transplant outcomes in MDS should focus on
incorporating molecular data into treatment algorithms
for accurate and earlier identification of higher-risk MDS
patients, initiating earlier donor search, use of alternative
donors, and modifying treatment strategies regarding
pretransplant cytoreduction and conditioning regimen
that can abrogate the effects of high risk chromosomal
abnormalities.
ACKNOWLEDGMENTS
Financial disclosure: The authors have nothing to disclose.
Conflict of interest statement: There are no conflicts of in-
terest to report.
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