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CRITICAL REVIEW
Allogeneic stem cell transplantation for patients with
myelodysplastic syndromes
Pongthep Vittayawacharin M.D.
1,2
| Piyanuch Kongtim M.D., Ph.D.
1
|
Stefan O. Ciurea M.D.
1
1
Hematopoietic Stem Cell Transplantation and
Cellular Therapy Program, Division of
Hematology/Oncology, Department of
Medicine, University of California Irvine, Irvine,
California, USA
2
Division of Hematology, Department of
Medicine, Faculty of Medicine Siriraj Hospital,
Mahidol University, Bangkok, Thailand
Correspondence
Stefan O. Ciurea, Hematopoietic Stem cell
Transplant and Cellular Therapy Program,
University of California, Irvine, 101 The City
Drive S, Bldg. 200, Rm. 450, Irvine, CA 92868,
USA.
Email: sciurea@hs.uci.edu
Abstract
Myelodysplastic syndromes (MDS) are a heterogenous group of clonal hematopoietic
stem cell neoplasms primarily affecting older persons, associated with dysplastic
changes of bone marrow cells, peripheral cytopenias, and various risk of leukemic
transformation. Although treatment with several drugs has shown improved disease
control, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the
only curative treatment for MDS. The number of patients receiving a transplant, as
well as survival, have increased past years because of the use of reduce-intensity
conditioning regimens (RIC) as well as the use of haploidentical donors for transplan-
tation. With treatment-related mortality as main limitation, pre-transplant evaluation
is essential to assess risks for this older group of patients. In a recent randomized
study, allo-HSCT with RIC for patients >50 years old with higher-risk MDS demon-
strated superiority in survival compared with hypomethylating agents. Genetic muta-
tions have been shown to significantly impact treatment outcomes including after
transplant. Recently, a transplant-specific risk score (which includes age, donor type,
performance status, cytogenetic category, recipient's cytomegalovirus status, per-
centage of blasts, and platelet count) has shown superiority in transplantation out-
come prediction, compared with previous scoring systems. Survival remains low for
most patients with TP53 mutations and novel treatment strategies are needed, such
as administration of natural killer cells post-transplant, as there is no clear evidence
that maintenance therapy after transplantation can improve outcomes.
1|INTRODUCTION
Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms
characterized by clonal proliferation of hematopoietic stem cells with
ineffective hematopoiesis leading to peripheral cytopenias and risk of
leukemic transformation.
1
Somatic mutations involving multiple bio-
logical pathways of hematopoietic cell development have been identi-
fied to be associated with pathogenesis of MDS, as well as to critically
impact the clinical phenotype, prognosis, and response to therapy.
2
Treatment of higher risk MDS relies primarily on hypomethylating
agents (HMA) or acute myeloid leukemia (AML)-type chemotherapy,
yet these cannot completely eradicate the MDS clone. Allogeneic
hematopoietic stem cell transplantation (allo-HSCT) remains the only
curative therapeutic option for patients with higher risk disease or
with high-risk features. According to data from the Center for Interna-
tional Blood and Marrow Transplant Research (CIBMTR), almost 7000
transplants for MDS have been performed in the United States during
the past decade, with significant improvement of outcomes over
time.
3
Even though several advances have been made in the field of
HSCT for MDS, transplant-related mortality (TRM) and relapse rate
remain high in some subgroups of patients. Therefore, careful selec-
tion of suitable transplant candidates is crucial. Disease characteristics
such as degree of cytopenia, percentage of bone marrow blasts, cyto-
genetic risk, presence of different molecular mutations, and patient
Received: 30 August 2022 Revised: 11 October 2022 Accepted: 12 October 2022
DOI: 10.1002/ajh.26763
322 © 2022 Wiley Periodicals LLC. Am J Hematol. 2023;98:322–337.wileyonlinelibrary.com/journal/ajh
characteristics such as performance status and comorbidity index,
influence survival after transplant. Relapse rate can be high in patients
with high-risk cytogenetics and/or associated TP53 mutations, hence
novel approaches to prevent relapse, at least in this high-risk group of
patients, are desperately needed. In this article, we comprehensively
review recent advances as well as discuss future directions of allo-
HSCT for MDS.
2|ADVANCES IN DISEASE RISK
STRATIFICATION
Prognostic systems for MDS have been developed with the aim of
guiding treatment, predicting progression to AML and survival, both
before and after transplant. In 1997, Greenberg et al. developed the
standard prognostic classification, so called International Prognostic
Scoring System (IPSS) using percentage of marrow blasts, cytoge-
netic risk, and number of cytopenias.
4
The IPSS score stratified
patients into four risk groups: low-, intermediate-1, intermediate-2,
and high-risk with significantly different survival and risk of AML
transformation. Due to its simplicity and superior predictive perfor-
mance compared with most available models, the IPSS has been
widely used to predict patient outcomes and guide treatment deci-
sion. Other prognostic scoring systems have been developed, such
as the World Health Organization (WHO) based Prognostic Scoring
System
5
and MD Anderson Cancer Center MDS risk model.
6
How-
ever, these prognosis systems are not broadly applied in clinical prac-
tice or clinical trials.
In 2012, with improved international MDS patient databases, a
revised version of the IPSS (IPSS-R) (Table 1A and B) was published.
7
Major refinements in the IPSS-R are the incorporation of the new five
cytogenetic risk groups, degree of cytopenias, and changes in the
cut-offs of marrow blasts; as a result, the IPSS-R re-stratified
MDS patients into five prognostic categories: very-low-, low-,
intermediate-, high-, and very-high-risk, which improved predictive
performance compared with the IPSS. Still, IPSS-R also has limitations
such as it can only be applied to untreated MDS patients, and does
not incorporate the impact of molecular mutations, recently it is found
to have prognostic relevance on clinical outcomes.
8
The incorporation of molecular mutations in the IPSS [IPSS-Molecular
(IPSS-M)] was introduced in 2022 as clinical-molecular prognostic
model for risk stratification and treatment decisions. The IPSS-M
includes clinical parameters (hemoglobin, platelet count, bone marrow
blasts), IPSS-R cytogenetic risk and the presence of somatic mutations
in 31 genes. The IPSS-M stratifies patients into six risk groups includ-
ing, very-low-, low-, moderate-low-, moderate-high-, high-, and very-
high-risk with differences in leukemia-free survival (LFS), leukemic
transformation, and overall survival (OS) as summarized in Table 2A
and B. Compared with the IPSS-R, IPSS-M increased concordance
index (C-index) more than 5 percentage points for all three clinical
outcomes and re-stratified 46% of the patients.
9
A summary of trans-
plant indications based on IPSS-R, IPSS-M, and other factors is pro-
vided in Table 3and Figure 1.
Even though, multiple studies have validated the IPSS and IPSS-R
in prediction of outcomes after allo-HSCT,
10
it is unclear whether the
IPSS-M can be successfully validated in patients receiving HSCT.
TABLE 1 (A) IPSS-R score (B) Risk stratification of IPSS-R score
7
Parameter Category score (score)
Cytogenetic
risk group
Very good:
Y, del
(11q) (0)
Good: Normal, del(5q), del
(12p), del(20q), double
including del(5q) (1)
Intermediate: del(7q), +8,
+19, i(17q), any other
single or double
independent clones (2)
Poor: 7, inv(3)/t(3q)/del
(3q), double including 7/
del(7q), complex: 3
abnormalities (3)
Very poor: Complex
with >3
abnormalities (4)
(A)
Marrow
blast
proportion
≤2% (0) >2%- <5% (1) 5%–10% (2) >10% (3) -
Hemoglobin ≥10 g/dl (0) 8- <10 g/dl (1) <8 g/dl (1.5) - -
Absolute
neutrophil
Count
≥0.8 10
9
/L
(0)
<0.8 10
9
/L (0.5) - - -
Platelet
count
≥100 10
9
/L
(0)
50-<100 10
9
/L (0.5) <50 10
9
/L (1) - -
Risk category Total score Median survival (years) Time until 25% of patients develop AML (years)
(B)
Very low ≤1.5 8.8 Not reached
Low >1.5–3 5.3 10.8
Intermediate >3–4.5 3.0 3.2
High >4.5–6 1.6 1.4
Very high >6 0.8 0.73
Abbreviations: AML, acute myeloid leukemia; IPSS-R, revised international prognostic scoring system.
VITTAYAWACHARIN ET AL.323
Additionally, none of transplant-specific factors are accounted for in
these models, and more importantly, lack predictability of dynamic
changes limiting their applicability in HSCT setting.
11
Recently, Nazha et al. developed a personalized prediction model
using a machine learning method by incorporating genetic mutations
as well as clinical parameters to predict OS and leukemia transforma-
tion in MDS patients.
12
The strength of this genomic data integrated
prognosis system is its ability to predict survival of patients receiving
different treatments precisely and can be used dynamically. To trans-
late this model into a useful clinical tool, the authors provided an
online calculator. Unfortunately, it seems to be inaccessible at
present. Moreover, like the above-mentioned models, transplant-
related factors are not accounted for in this model.
To emphasize the importance of transplant-related factors in
post-transplant outcome prediction, several transplant-specific prog-
nostic models have also been developed. Using data from the
European Society for Blood and Marrow Transplantation (EBMT) reg-
istry, seven factors were identified as independent predictors for
post-transplant survival, including age ≥50 years, use of a matched
unrelated donor (MUD), Karnofsky Performance Status (KPS) <90%,
very poor-risk cytogenetics or monosomal karyotype, positive cyto-
megalovirus status of the recipient, peripheral blood blasts >1%, and
TABLE 2 (A) IPSS-M score (B) Risk stratification of IPSS-M score
9
Category and variable
Adjusted hazard
ratio (95% CI)
Model
weight
(A)
Clinical
Marrow blasts (%) 1.07 (1.05–1.09) 0.0704
Platelets (10
9
/L) 0.998 (0.997–
0.999)
0.00222
Hemoglobin (g/dl) 0.84 (0.81–0.88) 0.171
Cytogenetic
IPSS-R cytogenetic category 1.33 (1.21–1.47) 0.287
Gene main effects
TP53
multihit
3.27 (2.38–4.48) 1.18
MLL
PTD
2.22 (1.49–3.32) 0.798
FLT3
ITD+TKD
2.22 (1.11–4.45) 0.798
SF3B1 with isolated del(5q) 1.66 (1.03–2.66) 0.504
NPM1 1.54 (0.78–3.02) 0.430
RUNX1 1.53 (1.23–1.89) 0.423
NRAS 1.52 (1.05–2.20) 0.417
ETV6 1.48 (0.98–2.23) 0.391
IDH2 1.46 (1.05–2.02) 0.379
CBL 1.34 (0.99–1.82) 0.295
EZH2 1.31 (0.98–1.75) 0.270
U2AF1 1.28 (1.01–1.61) 0.247
SRSF2 1.27 (1.03–1.56) 0.239
DNMT3A 1.25 (1.02–1.53) 0.221
ASXL1 1.24 (1.02–1.51) 0.213
KRAS 1.22 (0.84–1.77) 0.202
SF3B1 without comutations in
BCOR,BCORL1,RUNX1,
NRAS,STAG2,SRSF2, and del
(5q)
0.92 (0.74 1.16) 0.0794
Gene residuals
The number of residual
mutations: BCOR,BCORL1,
CEBPA,ETNK1,GATA2,
GNB1,IDH1,NF1,PHF6,
PPM1D,PRPF8,PTPN11,
SETBP1,STAG2, and WT1
1.26 (1.12–1.42) 0.231
TABLE 2 (Continued)
Risk category
Median
LFS
(years)
Median
OS
(years)
AML-transformation by
1, 2,4 years (%)
(B)
Risk category
Median
LFS
(years)
Median
OS
(years)
AML-transformation by
1, 2,4 years (%)
(B)
Very low 9.7 10.6 0, 1.2, 2.8
Low 5.9 6.0 1.7, 3.4, 5.1
Moderate low 4.5 4.6 4.9, 8.8, 11.4
Moderate high 2.3 2.8 9.5, 14.0, 18.9
High 1.5 1.7 14.3, 21.2, 29.2
Very high 0.76 1.0 28.2, 38.6, 42.8
Note: IPSS-M score =1.15467 +(P
variables j
w
j
x
j
)/log (2), where w
j
denotes the weight of variable j, and x
j
the value of the variable j observed
in a given patient.
Abbreviations: AML, acute myeloid leukemia; CI, confidence interval;
IPSS-M, molecular international prognostic scoring system; IPSS-R, revised
international prognostic scoring system; OS, overall survival; LFS,
leukemia-free survival.
TABLE 3 Transplant indications
Transplant indications
Level of
evidence
Newly diagnosed intermediate-2 or high-risk MDS
by IPSS-R as soon as possible
A
Any IPSS-R risk if:
1. Severe/additional cytopenia and
transfusion dependency
2. High risk molecular mutations or acquistion of
high-risk mutations
3. Failure of hypomethylating agents
4. Increase % bone marrow blasts
D
C
C
C
High or very-high risk MDS by IPSS-M
a
D
Therapy-related MDS C
Abbreviations: IPSS-R, revised international prognostic scoring system;
IPSS-M, molecular international prognostic scoring system; MDS,
myelodysplastic syndromes.
a
Likely similar with IPSS-R yet no prospective studies performed to date.
324 VITTAYAWACHARIN ET AL.
platelet count ≤50 10
9
/L before transplantation (Table 4A, B).
Weighted scores were assigned based on their impact on OS post-
transplant to generate four risk categories with OS ranges from 43%
to less than 10%.
13
The EBMT transplant-specific risk score for MDS
had a higher predictive performance (C-index of 0.609) comparing
with the previously developed transplant-specific scoring systems
such as the Gruppo Italiano Trapianto di Midollo Osseo (GITMO)
(C-index of 0.579) and the CIBMTR scoring system (C-index of
0.555).
13–15
However, more reports on external validation are needed
to confirm these findings.
With the advances in modern technologies that detect genetic
mutations, the future of MDS prognostication will focus on incorpo-
rating these data to help better predict transplant outcomes.
3|IMPACT OF MOLECULAR MUTATIONS
ON TRANSPLANT OUTCOMES
Using high-throughput genomic sequencing technologies, multiple
recurrent molecular mutations involving different pathways of cell
development and differentiation, including RNA splicing (SF3B1,
SRSF2,U2AF1), epigenetic regulators (DNMT3A,TET2,IDH1/2), chro-
matin modifiers (EZH2,ASXL1), transcriptional factors (RUNX1,TP53),
and signal transduction pathways (JAK2,NRAS/KRAS), have been iden-
tified in majority of MDS patients, with 80%–90% of these patients
having at least one genetic mutation.
16–18
The six most common
mutated genes in MDS are TET2 (33.7%), SF3B1 (32.9%), ASXL1
(27.0%), SRSF2 (17.6%), DNMT3A (13.5%), and RUNX1 (10.8%).
18
Data
of molecular mutations can be used to redefine prognosis for patients
with MDS. Presence of at least one of the following mutations - TP53,
EZH2,RUNX1,ASXL1,orETV6 has been shown to be associated with
significantly worse survival in all IPSS-R risk categories.
19
Multiple
other mutations have also been identified to be correlated with worse
survival, such as FLT3,KMT2A,BCOR,STAG2, and U2AF1.
8,9
Not only
the type of mutations but the total number of oncogenic mutations is
also associated with outcome. Papaemmanuil and colleagues showed
a progressive decrease in LFS with increased number of genetic muta-
tion or cytogenetic abnormalities. Presence of at least one mutation
significantly worsen the survival for all IPSS risk groups.
17
To date, the only molecular mutation shown to confer a more
favorable prognosis is mutation of SF3B1 gene. This mutation is found
in approximately 20% of patients with MDS and 65% of cases of
refractory anemia with ring sideroblasts (RARS) and is associated with
downregulation of mitochondrial signaling pathways. Patients with
SF3B1 mutation have significantly better event-free survival (EFS)
than those with unmutated gene, especially in patients without co-
mutations in BCOR,BCORL1,RUNX1,NRAS,STAG2,SRSF2, and del
(5q).
9,20
Several somatic mutations have been shown to be associated
with poor survival outcomes after transplantation. In a CIBMTR study,
FIGURE 1 MDS treatment algorithm
VITTAYAWACHARIN ET AL.325
a significantly shorter survival was observed in patients with TP53
mutation [hazard ratio (HR) 1.71; p< .001], and a shorter time to
relapse was noted both with TP53 mutation (HR 2.03; p< .001) and
RAS pathway mutations (HR 1.56; p=.002), while JAK2 mutation was
associated with risk of TRM (HR 2.10; p< .001).
16
Due to significant impact on disease prognosis, SF3B1 mutation
and biallelic TP53 inactivation were grouped in MDS with defining
genetic abnormalities which also included MDS with 5q deletion,
according to the recent 5th edition of the WHO classification.
21
Impact of conditioning regimen intensity was also evaluated in
patients with high-risk molecular mutations. The median survival in
TP53 mutated MDS patients was similar between myeloablative con-
ditioning regimens (MAC) and reduced-intensity conditioning regi-
mens (RIC) (7.5 months and 9.2 months, respectively; p=.19), while
the relapse rate for RAS pathway mutations patients was higher in RIC
compared with non-mutation in RAS pathway mutations (42% and
20%, respectively; p< .001), with no difference in relapse rate for
patients with RAS pathway mutations versus wild-type using MAC
(22% and 15%, respectively; p=.31). Both MAC and RIC had higher
1-year non-relapse mortality (NRM) in patients with JAK2 mutation
compared with non-JAK 2 mutation (MAC 53% and 25%; p=.007,
RIC 50% and 28%; p=.003 respectively).
16
Similar results were reported by Yoshizato and colleagues. TP53-
mutated MDS patients and RAS pathway-mutated MDS/MPN
patients had adverse survival outcome post-transplant, especially
those with TP53 mutation and complex cytogenetics. The median OS
after transplantation in this group was only 4.8 months, while median
OS in TP53 without complex cytogenetic was not reached.
22
Apart
from TP53 and RAS pathway mutations, EZH2 mutations with allelic
frequencies ≥33% were shown to have poor OS (HR 8.42; p< .0001)
and relapse-free survival (RFS) (HR 6.57; p=.003) in a recent
CIBMTR study.
23
In a study by Ciurea et al., TP53-mutated AML/MDS patients
with HCT-CI >4, KPS ≤80% and not in complete remission 1 or 2 at
TABLE 4 (A) Seven independent risk
factors from EBMT transplant-specific
risk score in MDS after allo-HSCT (B)
Risk stratification of EBMT transplant-
specific risk score in MDS after
allo-HSCT
13
Factor Hazard ratio (95% CI) pScore value
(A)
Age at transplant, years
<50 Reference
≥50 1.71 (1.39–2.09) <.001 2
Blood blasts at transplant, %
≤1 Reference
>1 1.39 (1.03–1.86) .03 1
Platelet at transfusion 10
9
/L
>50 Reference
≤50 1.46 (1.17–1.82) .001 1
Donor type
HLA-identical sibling Reference
Matched unrelated 1.39 (1.13–1.71) <.001 1
Cytogenetic risk
Very good to poor Reference
Very poor/monosomal karyoptype 1.71 (1.43–2.06) <.001 2
CMV serostatus of recipient
Negative Reference
Positive 1.39 (1.16–1.65) <.001 1
KPS, %
90 to 100 Reference
<90 1.44 (1.20–1.72) <.001 1
Risk group Hazard ratio for death (95% CI) Survival rates
(B)
Low (0–1) Reference 68.7%
Intermediate (2–3) 2.02 (1.41–2.90) 43.2%
High (4–5) 3.49 (2.45–4.97) 26.6%
Very high (>5) 5.90 (4.01–8.67) 9.5%
Abbreviations: allo-HSCT, allogeneic hematopoietic stem cell transplantation; CI, confidence interval;
CMV, cytomegalovirus; EBMT, the European Society for Blood and Marrow Transplantation; HLA,
human leukocyte antigen; KPS, karnofsky performance status scale; MDS, myelodysplastic syndromes.
326 VITTAYAWACHARIN ET AL.
transplantation had worse outcomes. Assigning a score for each vari-
ables, the authors created three prognostic groups of patients with
different 1-year survival ranging from 67% to 17%, suggesting that
patients with more than two factors may not be good transplant
candidates.
24
Therapy-related MDS (t-MDS) has been, in general associated with
worse outcomes. However, Aldoss et al. found comparable OS and RFS
after transplantation for t-MDS patients with and without TP53 muta-
tion. Moreover, other high risk mutations reported in MDS except
TP53,suchasEZH2,ETV6,RUNX1,andASXL1 did not seem to affect
OS and RFS in patients with t-MDS receiving transplantation, yet the
number of patients analyzed in this study was relatively small.
25
Taken together, these data clearly demonstrate significant impact
of genetic alterations on outcomes of MDS patients. Select subsets of
patients with high-risk molecular mutations may preferentially benefit
from allo-HSCT. However, inadequate long-term disease control
remains a fundamental problem, and novel strategies to decrease
relapse are warranted.
4|ROLE OF TRANSPLANTATION IN MDS
Life expectancy of patients with MDS ranges from a few months to
several years depending on several patient- and disease-related fac-
tors. Allo-HSCT can offer the benefit from both high dose chemother-
apy and graft-versus-leukemia (GVL) effect, which could help
eradicate MDS clone and is currently the only potentially curative
therapy for MDS. Despite advances in transplantation, there is still
considerable morbidity and mortality associated with this treatment.
Therefore, selecting best candidates and timing for transplant proce-
dure is crucial to provide the maximum benefit.
According to a study by Cutler and colleagues evaluating the
expected survival with and without transplantation using a Markov
model, early transplantation at the time of diagnosis for patients with
intermediate-2 and high IPSS was associated with maximal life expec-
tancy, while MDS patients with low- or intermediate-1 risk had longer
life expectancy if transplantation was delayed but performed before
leukemic progression.
26
Similarly, using IPSS-R, Della Porta et al.
found that life expectancy increased when HSCT was delayed from
the initial stages to intermediate IPSS-R risk and then decreased for
higher risks.
27
Results from both studies have substantially influenced
clinical practice. According to the recommendations from an interna-
tional expert panel, allo-HSCT should be performed as soon as possi-
ble for higher-risk MDS patients who are physically fit, with good
performance status and available donor. In lower-risk group, allo-
HSCT is recommended in patients with poor risk features, including
poor risk cytogenetics, profound cytopenias (neutrophil count
<0.3 10
9
/L, platelet count <30 10
9
/L), higher or increase in bone
marrow blasts (>50% increase or with >15% marrow blasts), high
transfusion requirements ≥2 units per month for 6 months,
28
or pres-
ence of high risk mutations.
19
Several retrospective studies compared transplantation with
HMA treatment (Table 5). Platzbecker et al.
29
reported results of a
retrospective cohort of patients with high-risk MDS treated with
transplantation versus HMA and showed that 2-year OS was 39%
(95% CI 30–50) in allo-HSCT group and 23% (95% CI 14–40) in the
azacytidine (AZA) group (HR 0.3, p=.007). In 2015, a prospective
cohort study demonstrated that 4-year OS in allo-HSCT group was
37% and only 15% in the non-transplantation group (p=.02).
30
Survival benefit from allo-HSCT is not only limited to young
patients with good performance status, but also in older patients. In a
prospective multicenter Blood and Marrow Transplant Clinical Trials
Network (BMT CTN 1102) clinical trial with biologic assignment,
Nakamura et al. compared RIC allo-HSCT with HMA treatment or
best supportive care in intermediate-2 or high-risk MDS patients ages
50–75. Treatment assignment was based on the availability of an HLA
matched donor. In an intention to treat analysis, an improvement in
survival was observed in the donor arm compared with the no-donor
group with the adjusted 3-year OS of 47.9% versus 26.6% (p=.0001)
TABLE 5 Summary of publications comparing outcomes of
allo-HSCT versus other types of treatments
Reference Method Results
Platzbecker
et al.
29
Retrospective cohort
study in high risk MDS
age 60–70 years
•Allo-HSCT (n=103)
•AZA (n=75)
2-year EFS 37% (95% CI
28–48) and 14% (95%
CI 7–27), respectively;
p=.04
2-year OS 39% (95% CI
30–50) and 23% (95%
CI 14–40),
respectively; p=.007
Robin
et al.
30
Prospective cohort study
in high risk MDS age
50–70 years
•HLA match
donor (n=112)
•No donor (n=50)
4-year OS 37% (95% CI
28–48) and 15% (95%
CI 6–39), respectively;
p=.02
Nakamura
et al.
31
Biologic assignment trial
in intermediate-2 or
high-risk MDS by IPSS
age 50–75 years
•RIC allo-
HSCT (n=260)
•HMA/BSC (n=124)
3-year OS 47.9% (95%
CI 41.3–54.1) and
26.6% (95% CI
18.4–35.6),
respectively;
p=.0001
Kröger
et al.
32
Prospective phase II
study in
intermediate-2 or high-
risk MDS by IPSS or
intermediate I with
high-risk cytogenetics
age 55–70 years
•RIC allo-
HSCT (n=81)
•AZA (n=27)
3-year EFS 34% (95% CI
22–47) and 0%,
respectively; p< .001
3-year OS 50% (95% CI
39–61) and 32% (95%
CI 14–52),
respectively; p=.12
Abbreviations: Allo-HSCT, allogeneic hematopoietic stem cell
transplantation; AZA, azacytidine; BSC, best supportive care; CI,
confidence interval; EFS, event-free survival; HLA, human leucocyte
antigen; HMA, hypomethylating agents; IPSS, international prognostic
scoring system; MDS, myelodysplastic syndromes; OS, overall survival;
RIC, reduced intensity conditioning regimen.
VITTAYAWACHARIN ET AL.327
and 3-year LFS in the allo-HSCT group of 35.8% versus 20.6%
(p=.003) respectively.
31
More recently, a prospective multicenter phase II (VidazaAllo)
study included higher risk MDS patients aged 55–70 years. The
patients who had HLA-matched donor received four cycles of AZA
and allo-HSCT. The result revealed that 3-year OS in allo-HSCT after
AZA induction was 50% (95% CI 39–61), whereas 3-year OS in the
continuous AZA group was 32% (95% CI 14–52; p=.12).
32
More-
over, this study showed that a third of patients receiving AZA induc-
tion treatment over 4 months did not make it to treatment
assignment, primarily due to disease progression, suggesting that
urgent transplantation is needed as soon as the donor is available.
Sixty-five percent of patients who received a transplant in this study
had an unrelated donor. Delays in donor acquisition likely contributed
to disease progression, at least in some of these patients.
These results come in the context of improved survival over time
with transplantation for patients with MDS, including for patients
above age 70.
33
Most recent data from the CIBMTR demonstrated
that 3-year OS in MDS patients significantly increased from 38% dur-
ing 2001–2005 to 49% between 2016 and 2019.
3
The upper limit in BMT CTN 1102 study was 75 years.
31
How-
ever, transplant eligibility is a complex issue and, in general, chrono-
logical age should not be solely used as eligibility restriction. A
comprehensive geriatric assessment combining multiple health
domains, including comorbidity index (HCT-CI), performance status,
physical function, cognition, psychological evaluation, nutritional sta-
tus, social support, medication review, and biomarkers
34
can detect
vulnerable patients who are not be identified by only performance
status assessment.
35
Systematic evaluation of older patients using
geriatric assessment may improve transplant outcomes compared
with historical data.
34
Not only in elderly individuals but a similar comprehensive assess-
ment has been shown to be beneficial in younger transplant candi-
dates who previously received multiple lines of treatment prior
allo-HSCT.
36
5|CONDITIONING REGIMENS FOR
TRANSPLANTATION
MDS is primarily a disease of older individuals in which more than half
of the patients affected by the disease are over the age of 60. For this
reason, most of these patients are not a suitable candidate of allo-
HSCT using MAC regimens. With the development of RIC regimens,
allo-HSCT now can be offered for the majority of MDS patients.
Not surprisingly, several studies have shown that RIC allo-HSCT
is associated with lower TRM but higher relapse rate compared with
transplantation using MAC, resulting in comparable survival. A retro-
spective study from the EBMT revealed that 13-year relapse rate of
patients receiving RIC allo-HSCT was higher at 48%, compared with
MAC at 31% (HR 1.5; 95% CI 1.1–1.9; p=.04). The OS (27% in RIC
and 30% in MAC; p=.4) and PFS (21% in RIC and 29% in MAC;
p=.3) were similar.
37
Stratified by disease risk, a recent CIBMTR
retrospective study showed that AML/MDS patients with low to
intermediate disease risk index (DRI) had worse disease-free survival
(DFS) with RIC compared with MAC (HR 1.19; 95% CI 1.07–1.33;
p=.001) but comparable OS, due to higher rate of relapse, offset a
benefit of lower NRM. However, in the high to very high-risk DRI
patients, results were similar between the two groups both for DFS
and OS.
38
A major problem is the fact that the RIC group encom-
passes a wide range of conditioning regimens from very light non-
ablative to similar to ablative conditioning, such as fludarabine and
melphalan 140 mg/m
2
(Flu/Mel140), which makes interpretation of
results very difficult. Moreover, there are concerns regarding inherent
patient selection bias in these retrospective comparisons.
According to a prospective phase III randomized study from the
EBMT (RICMAC trial), which compared RIC with MAC in MDS
patients who had blasts <20% at the time of transplantation (median
blast count 4% in MAC and 5% in RIC), clinical outcomes, including
engraftment, graft-versus-host disease (GHVD), NRM, relapse rate,
RFS and OS were all equivalent.
39
Conversely, BMT CTN 0901 pro-
spective randomized trial, which included AML and MDS patients
between 18–65 years with less than 5% marrow myeloblasts, pro-
vided evidence that OS in patients in the MAC group was superior
compared with the RIC group (HR 1.54; 95% CI 1.07–2.2; p=.03).
Significantly higher relapse rate was observed in the RIC group
(HR 4.06; 95% CI 2.59–6.35; p< .001), whereas higher TRM was
found in the MAC group (HR 2.00; 95% CI 1.06–3.70; p=.03). How-
ever, great majority of patients in the RIC group had fludarabine and
2 days of busulfan (Flu/Bu2) regimen, which was associated with
higher relapse rate, while patients receiving Flu/Mel140 had similar
disease-free survival with MAC (68% vs. 61.9% respectively).
40
With a median age at diagnosis for MDS patients of 76 years in
the United States,
41
RIC is the most used conditioning regimen, as
MAC is associated with prohibitive TRM. A recent CIBMTR compari-
son of two of the most used RIC conditioning regimens including Flu/-
Mel140 and reduced Flu/Bu for MDS patients at least 60 years of
age, showed that patients receiving Flu/Mel140 had lower relapse
incidence (26% and 44%; p≤.0001) but higher TRM (26% and 16%;
p≤.0001); overall, patients receiving FM140 regimen had a better
3-year DFS (35% vs. 27%; p=.01) and 3-year OS (46% vs. 39%;
p=.03) respectively.
42
Our group has tried to understand which
patients do not do well with FM140 regimen and used a lower inten-
sity conditioning with melphalan 100 mg/m
2
which is very well-
tolerated and could probably improve TRM and survival.
43
An augmented intensity RIC regimen, FLAMSA-Bu (fludarabine/
cytarabine/amsacrine/busulfan) was reported in a phase II randomized
study comparing with conventional fludarabine-based RIC in high-risk
AML and MDS patients. Two-year EFS and OS were comparable
between FLAMSA-Bu and RIC regimens (2-year EFS 54.2% and
48.7%; p=.83, 2-year OS 60.9% and 58.8%; p=.81 respectively).
Moreover, measurable residual disease clearance at day 42 was not
different between the two treatment groups.
44
Due to its presumed more favorable organ toxicity profile, treosul-
fan has been incorporated in conditioning regimens for allo-HSCT. A ret-
rospective study from the EBMT registry for MDS patients showed that
328 VITTAYAWACHARIN ET AL.
treosulfan in combination with fludarabine (Tre/Flu) was associated with
lower risk of relapse (HR 0.55; p< .001) and higher OS (HR 0.72;
p=.01) when compared with other MAC and other RIC regimens.
45
Recently, a phase III randomized study was published, which compared
RIC Tre/Flu and Flu/Bu2 RIC regimen for AML/MDS patients, 50–
70 years or younger patients with significant comorbidities (HCT-CI >2).
The results revealed that 3-year EFS and OS were superior in the
Tre/Flu group (59.5% and 49.7%; p=.0006, OS 66.8% and 56.3%;
p=.0037 respectively).
46
However, it remains unclear if treosulfan-
based conditioning can outperform other commonly used melphalan-
based containing regimens. A summary of conditioning regimens used
for transplantation of MDS patients is presented in Table 6.
TABLE 6 Summary of publications comparing outcome of allo-HSCT using different conditioning regimen intensities (selected studies)
Reference Method Results
Martino
et al.
37
Retrospective cohort study in allo-HSCT
MDS patients
•MAC (n=630)
•RIC (n=213)
13-year CIR 31% (95% CI 27–35) and 48% (95% CI 42–57); p=.04
13-year PFS 29% (95% CI 25–33) and 21% (95% CI 15–26), respectively; p=.06
13-year OS 30% (95% CI 26–34) and 27% (95% CI 22–34), respectively; p=.4
Bejanyan
et al.
38
Retrospective study
•RIC and low/intermediate DRI (n=999)
•MAC and low/intermediate DRI
(n=1539)
•RIC and high/very high DRI (n=728)
•MAC and high/very high DRI (n=1121)
RIC compared with MAC in low/intermediate DRI
DFS: HR 1.19 (95% CI 1.07–1.33; p=.001)
OS: HR 1.11 (95% CI 0.99–1.25; p=.06)
RIC compared with MAC in high/very high DRI
DFS (HR 1.07 95% CI 0.96–1.19; p=.24)
OS (HR 1.0 95% CI 0.90–1.12; p=.98)
Kröger
et al.
39
Prospective randomized phase III study
•MAC (n=64)
•RIC (n=65)
1-year NRM 25.3% (95% CI 14.6–36) and 16.9% (95% CI 7.8–26), respectively;
p=.29
2-year RFS 58.3% (95% CI 46–70.6) and 62.4% (95% CI 50.4–74.4), respectively;
p=.58
2-year OS 63.2% (95% CI 51.1–75.2) and 76.3% (95% CI 65.8–86.9), respectively;
p=.08
Scott et al.
40
Prospective randomized phase III study
•MAC (n=54)
•RIC (n=72)
4-years TRM 25.1% (95% CI 18–32.9) and 9.9% (95% CI 5.3–15.6), respectively;
p< .001
4-year RFS 57.9% (95% CI 49.7–66.2) and 33.7% (95% CI 25.7–41.6), respectively;
p< .0001
4-year OS 62% (95% CI 53.5–70.1) and 49% (95% CI 40.7–57.2), respectively;
p=.022
Oran et al.
42
Retrospective study
•FluBu (n=597)
•FluMel (n=448)
3-year relapse incidence 50% (95% CI 46–54) and 32% (95% CI 27–37), respectively;
p< .0001
3-years TRM 28% (95% CI 24–33) and 36% (95% CI 31–41), respectively; p=.03
3-year DFS 27% (95% CI 23–31) and 35% (95% CI 30–40), respectively; p=.01
3-year OS 39% (95% CI 34–43) and 46% (95% CI 41–51), respectively; p=.03
Ciurea
et al.
43
Retrospective study
•FluMel100 (n=89)
•FluMel140 (n=78)
•FluBu ≥20 000 (n=131)
•FluBu16000 (n=106)
3-year NRM 19%, 39%, 35%, and 21%, respectively; p=.06
3-year relapse rate 32%, 32%, 30%, and 55%, respectively; p=.003
5 year- PFS 49%, 30%, 34%, and 23%, respectively; p=.02
5-year GRFS 28%, 20%, 18%, and 9%, respectively; p=.006
Craddock
et al.
44
Prospective randomized phase II study
•Flu-RIC (n=122)
•FLAMSA-Bu (n=122)
1-year TRM 16.8% and 20.5%, respectively; p=.53
2-year EFS 48.7% and 54.2%, respectively; p=.82
2-year OS 58.8% and 60.9%, respectively; p=.81
Shimoni
et al.
45
Retrospective study
•Tre/Flu (n=367)
•RIC (n=687)
•MAC (n=668)
5-year NRM 30% (95% CI 25–35), 27% (95% CI 23–30), 34% (95% CI 31–38),
respectively; p=.008
5-year relapse rate 25% (95% CI 21–30), 38% (95% CI 34–42), 25% (95% CI 22–29),
respectively; p< .001
5-year OS 50% (95% CI 44–54), 43% (95% CI 38–47), 43% (95% CI 39–47),
respectively; p=.03
Beelen
et al.
46
Phase III, randomized parallel study
•Tre/Flu (n=268)
•Bu/Flu (n=283)
3-year EFS 59.5% and 49.7%, respectively; p=.0006
3-year OS 66.8% and 56.3%, respectively; p=.0037
Abbreviations: Allo-HSCT, allogeneic hematopoietic stem cell transplantation; Bu, busulfan; CI, confidence interval; CIR, cumulative incidence of relapse;
DFS, disease-free survival; DRI, disease risk index; EFS, event-free survival; FLAMSA-Bu, fludarabine/cytarabine/amsacrine/busulfan; Flu, fludarabine;
GRFS, graft-versus-host disease free, relapse-free survival; HR, hazard ratio; MAC, myeloablative conditioning regimens; Mel, melphalan; MDS,
myelodysplastic syndromes; NRM, non-relapse mortality; OS, overall survival; PFS, progression-free survival; RFS, relapse-free survival; RIC, reduced
intensity conditioning regimen; Tre, treosulfan; TRM, transplant-related mortality.
VITTAYAWACHARIN ET AL.329
6|DONOR TYPE
To date, majority of donors used for transplantation are HLA-matched
related (MRD), MUD and, more recently, haploidentical related donors.
Transplant outcomes for MDS patients based on different donor types
were evaluated in several studies (Table 7). Saber et al. analyzed the
outcomes of patients with MDS from three donor types including
MRD, MUD and seven of eight MUD using the CIBMTR database. In
multivariate analysis, there was lower TRM in MRD group compared
with MUD and seven of eight MUD group [relative risk (RR) 1.44;
p=.007], with no difference in relapse rate. DFS was worse with a
seven of eight MUD compared with MRD (RR 1.47; p=.08) and MUD
(RR 1.29; p=.04), with no difference in survival between MRD and
MUD groups.
47
Despite very good outcomes with MRD transplants,
these donors are not available for most MDS patients. MUD donors are
also limited for patients with race other than Caucasians, for whom
haploidentical donors are most important to be considered.
Haploidentical donors have been increasingly utilized for trans-
plantation including for MDS patients.
3
Wang et al. reported registry
outcomes comparing haploidentical and MRD transplants for MDS.
Results showed that 4-year cumulative incidence of NRM was signifi-
cantly higher in three of six and four of six haploidentical group com-
pared with MRD group (34%, 29%, 16%,respectively; p=.004), but
4-year cumulative incidence of relapse (CIR), RFS, and OS were not
significantly different between these three groups.
48
Another retro-
spective study from EBMT showed better 2-year survival with MRD
over haploidentical transplants (2-year PFS 51% and 47%; p=.029,
2-year OS 58% and 50%; p≤.001, respectively).
49
In addition, a
recent CIBMTR study comparing outcomes of haploidentical and
MUD transplants showed that there was higher relapse rate (HR 1.56;
95% CI 1.12–2.16; p=.008) and lower DFS (HR 1.29; 95% CI
1.01–1.65; p=.042) in haploidentical compared with MUD trans-
plants, owing primarily to the use of non-myeloablative conditioning
regimens in the haploidentical donor group versus mostly fludarabine
and an alkylating agent for MUD transplants. However, there was no
difference in 2-year OS between the two groups (46% for haploidenti-
cal and 44% for MUD group; p=.65) with lower incidence of grade
2 to 4 acute GVHD (HR 0.44; p< .001) and chronic GVHD (HR 0.36;
p< .0001) in haploidentical transplants with post-transplantation
cyclophosphamide as GVHD prophylaxis, suggesting that haploidenti-
cal transplants can be considered for patients who do not have an
HLA matched donor or need to proceed urgently to transplantation.
50
Using data from the EBMT registry, Robin and colleagues also
compared outcomes of mismatched donor transplants for patients
with MDS [umbilical cord blood (UCB), 9/10 MUD and haploidentical]
and found that DFS was better with a haploidentical donor versus
UCB due to lower NRM with no difference comparing with mis-
matched unrelated donor.
51
TABLE 7 Summary of publications on donor type
Reference Method Results
Saber et al.
47
Retrospective study in MDS
patients
•MRD (n=176)
•8/8 MUD (n=413)
•7/8 MUD (n=112)
3-year TRM 29% (95% CI 22–35), 41% (95% CI 36–46; p=.003), 42% (95% CI 33–51; p=.01)
respectively
- 3-year DFS 41% (95% CI 34–48), 35% (95% CI 30–40; p=.16), 29% (95% CI 21–37; p=.02)
respectively
- 3-year OS 47% (95% CI 40–55), 38% (95% CI 34–43; p=.04), 31% (95% CI 22–39; p=.003)
respectively
Wang et al.
48
Retrospective study in MDS
patients
•3/6 haploidetical (n=136)
•4–5/6 haploidetical (n=90)
•MRD (n=228)
4-year NRM 34% (95% CI 26–34), 29% (95% CI 20–39), 16% (95% CI 12–21), respectively;
p=.004
4-year RFS 58% (95% CI 50–67), 63% (95% CI 54–73), 71% (95% CI 65–77), respectively;
p=.14
4-year OS 58% (95% CI 50–67), 63% (95% CI 54–73), 73% (95% CI 67–79), respectively;
p=.07
Raj et al.
49
Retrospective study in MDS
patients
•MRD (n=1414)
•Haploidetical (n=415)
2-year NRM 20% (95% CI 17–22) and 30% (95%CI 25–35), respectively; p< .001
2-year PFS 51% (95% CI 48–54) and 47% (95%CI 42–53), respectively; p=.029
2-year OS 58% (95% CI 55–61) and 50% (95% CI 45–55), respectively; p< .001
Grunwald el
at.
50
Retrospective study in MDS
patients
•Haploidetical (n=176)
•MUD (n=427)
2-year NRM 24% (95% CI 18–31) and 34% (95% CI 30–39), respectively; p=.57
2-year DFS 29% (95% CI 21–37) and 36% (95% CI 31–41), respectively; p=.042
2-year OS 46% (95% CI 37–54) and 44% (95% CI 39–48), respectively; p=.65
Robin et al.
51
Retrospective study in MDS
patients
•Haploidetical (n=222)
•MMUD (n=443)
•Cord blood (n=168)
3-year NRM 36% (95% CI 27–44), 40% (95% CI 35–45; p=.22), 48% (95% CI 39–57;
p=.007) respectively
3-year PFS 43% (95% CI 36–51), 33% (95% CI 28–38; p=.056), 29% (95% CI 22–37; p=.003)
respectively
3-year OS 47% (95% CI 40–56), 38% (95% CI 33–43; p=.082), 31% (95% CI 25–40; p=.002)
respectively
Abbreviations: CI, confidence interval; DFS, disease-free survival; MDS, myelodysplastic syndromes; MMUD, mismatch unrelated donor; MRD, match
related donor; MUD, match unrelated donor; NRM, non-relapse mortality; OS, overall survival; RFS, relapse-free survival; TRM, transplant-related
mortality.
330 VITTAYAWACHARIN ET AL.
Owing to its near-universal availability and comparable outcomes,
number of transplants performed using a haploidentical donors has
steadily increased worldwide in recent years.
7|SOURCES OF HEMATOPOIETIC STEM
CELLS
The stem cell source has also been evaluated in patients receiving
transplantation for MDS. In general, due to a higher number of T-
lymphocytes in peripheral blood stem cells (PBSCs), a faster engraft-
ment has been noted with concern for higher rates of chronic GVHD
comparing with bone marrow stem cells (BMSCs).
52
A retrospective
study in patients receiving MRD transplantation for MDS, patients
who received PBSCs had faster neutrophil recovery by day
14 (RR 4.28; 95% CI 2.53–7.24) and faster platelet recovery by day
30 (RR 3.21; 95% CI 2.15–4.80) when compared with BMSCs. The
incidence of both of acute and chronic GVHD were not significantly
different between these two sources of stem cells. The 2-year TRM
and treatment failure were lower in PBSCs group (RR 0.33; p< .007
and RR 0.22; p< .001 respectively). Use of PBSCs tended to be asso-
ciated with improved 2-year EFS and OS, but the differences did not
reach statistical significance (EFS 50% vs. 39%; p=.2 and OS 58%
vs. 49%; p=.4).
53
Similar results were noted in patients receiving haploidentical
transplants. The use of BMSCs did not demonstrate differences in
neutrophil recovery by day 28 compared with PBSCs (85% and 91%;
p=.11) but platelet recovery by day 100 was lower in the BMSCs
group (78% and 86%; p=.04). There were no differences in the inci-
dences of day-100 grade 2 to 4 acute GVHD (BMSCs 27% and PBSCs
23%; p=.64), 2-year chronic GVHD (BMSCs 15% and PBSCs 25%;
p=.19), and no survival differences between the two groups.
50
8|ROLE OF INDUCTION TREATMENT
BEFORE TRANSPLANTATION
Previously reported data form CIBMTR have demonstrated that the
number of blasts at the time of transplantation affected post-
transplantation relapse risk, especially in patients with blasts more
than 20%, who had relapse risk 6.3 times higher than patients with
blasts less than 5% (p< .0001).
54
Due to their acceptable toxicity profile when compared with con-
ventional intensive AML-type induction chemotherapy, the HMA
have been preferably used for pre-transplant disease debulking with
the ultimate goal of reducing relapse risk and prolonging post-
transplant survival. Furthermore, pre-transplant HMA treatment might
offer benefit in enhancing the GVL effect as preclinical studies have
shown that it is associated with an increased expression of killer-cell
immunoglobulin-like receptors,
55
minor histocompatibility antigens,
56
and various tumor antigens.
57
In general, induction therapy has been offered for patients with
excess blasts at diagnosis, but the role for pre-transplant debulking for
the subgroup of patients with higher-risk MDS remains controversial.
Moreover, treatment-related complications, such as prolonged myelo-
suppression, development of a severe infection or organ dysfunction
might affect the ability of proceeding to transplantation. According to
the recommendations from an international expert panel, reducing the
blast count could be considered when marrow blasts are more than
10%, especially when transplantation using non-myeloablative condi-
tioning regimen is planned.
28
However, a retrospective study by Schroe-
der and colleagues demonstrated that there was no difference in 5-year
OS, RFS, CIR, and NRM in MDS patients with marrow blast count more
than 5% at diagnosis or secondary AML treated with three treatment
protocols prior to transplantation including directly upfront transplanta-
tion, intensive chemotherapy (ICT), and treatment with HMA. Similar
results were found in a subgroup analysis of patients with ≥10% marrow
blasts.
58
Another retrospective study form the EBMT has demonstrated
similar post-transplantation outcomes for patients who received HMA
or ICT prior to transplant. The 3-year OS, RFS, CIR, and NRM were not
significantly different between these two treatment options.
59
A meta-analysis of seven studies showed no survival differences
between patients with MDS treated with pre allo-HSCT HMA and
those receiving pre allo-HSCT best supportive care (HR =0.86, 95%
CI: 0.64–1.15, p=.32).
60
However, the fact that all studies included
in this meta-analysis were retrospective and with relatively small num-
bers of patients raises questions about significant biases that limit the
strength of the conclusions.
Despite lower toxicity with HMA comparing with ICT,
61
approxi-
mately 33% of higher-risk MDS patients aged between 55-70 years
with AZA induction could not continue treatment with transplantation
mostly due to disease progression, or other adverse events.
32
Addi-
tionally, pre-transplant therapy, both chemotherapy and HMA, was
associated with poor 2-year OS when disease relapsed after trans-
plantation compared with treatment naïve patients (19% and 59%;
p=.0001).
58
It is postulated that pretransplant therapy may influence
subclonal evolution or clonal selection.
62
As such, there is no good
evidence at present that treatment with HMA and/or chemotherapy
prior to transplant improves survival in these patients (Table 8).
9|RELAPSE AND MAINTENANCE
THERAPY AFTER TRANSPLANTATION
Relapse after allo-HSCT is still a major cause of treatment failure and
mortality. Data from EBMT showed that the median time between
allo-HSCT and relapse for patients with AML and MDS was
6.3 months (range 1–160.8), less than 20% of the patients with
relapse disease would survive beyond 2 years.
63
For this reason, post-
transplant monitoring with donor chimerism and measurable residual
disease assessment, is essential for early detection and possibly pre-
emptive treatment to prevent hematologic relapse.
64
It has been
shown that declining of lineage-specific donor cell chimerism (CD33+
or CD34+) or detection of measurable residual disease after allo-
HSCT in MDS patients were associated with an increased risk of
relapse.
65–67
Detection at least one mutation with a maximum variant
VITTAYAWACHARIN ET AL.331
allele frequency ≥0.5% at day 30 post-transplantation in MDS
patients significantly increased risk of disease progression (HR 4.48,
95% CI 2.21–9.08; p< .001) and lowered 1-year PFS (HR 2.39, 95%
CI 1.40–4.09; p=.002), compared with patients with mutation not
present.
68
Options for salvage therapy for post-transplant disease relapse
are limited and in general do not provide long-term disease control.
Motabi and colleagues published a retrospective study in such
patients and showed that ICT resulted in overall response rate (ORR)
of 37% and 1-year OS without donor lymphocyte infusion (DLI) was
only 16%.
69
Salvage therapy using AZA was also reported to provide
ORR in approximal one third of the patients with 1-year OS of only
25%.
70
DLI and second allo-HSCT in selected patients with relapsed
MDS or AML after first allo-HSCT can result in 2-year OS of 44.9%.
71
However, not many patients are eligible for a second transplant, and
careful selection of transplant procedures that can eradicate disease
without significant toxicity is extremely challenging. Myeloablative
conditioning should be avoided in early relapse disease especially in
those who had disease relapse within 6 months from the first trans-
plant. Allo-HSCT using stem cells from a different donor may be con-
sidered to potentially offer stronger GVL effect.
72
Enhancing the GVL effect without increasing GVHD and the
direct anti-leukemic effect are the expected qualifications of post-
transplantation maintenance therapy. AZA has been suggested to
expand regulatory T cells after transplantation possibly reducing
GVHD without interfering with the GVL effect.
73
Maintenance therapy using HMA has been reported to be well-
tolerated with mostly manageable hematological toxicities yet
improvement in survival comparing with observation remains elu-
sive.
74,75
(Table 8) Results from a phase III randomized study com-
paring outcomes of patients with high-risk MDS or AML receiving
post-transplant maintenance therapy with azacytidine versus no
intervention showed no significant difference in incidence of acute
GVHD (25.5% vs. 28.7%; p=.73), chronic GVHD (25.8%
vs. 30.8%), 1-year CIR (25.5% vs. 28.7%), median RFS (2.07 years
vs. 1.28 years; p=.43), and median OS (2.52 years vs. 2.56 years;
p=.85) between the two groups.
76
Most patients could not com-
plete the intended treatment due to development of cytopenia,
hence there is concern that, at the current dose of 32 mg/m
2
per
day subcutaneously for 5 days every 28 days for 12 cycles is still
too high to be able to apply consistently post-transplant. It is also
possible that, due to the fact that drop in counts for various rea-
sons post-transplant could make reliably application of HMA post-
transplant questionable.
A recent meta-analysis of 14 studies comparing post-transplant
maintenance with HMA versus observation in AML/MDS patients
showed lower CIR and NRM in the HMA maintenance group than the
observation group, which resulted in a superior OS and RFS in the
HMAs group with a pooled risk ratio of 1.38 and 1.46 respectively.
Overall, the incidences of grades 3 to 4 acute GVHD and chronic
GVHD did not differ in both groups. The survival benefits of HMA
maintenance persisted after excluding the seven studies using com-
bined HMA with either gemtuzumab ozogamicin (2 studies) or DLI
(5 studies). However, due to significant heterogeneity of the studies
included in this study, results should be carefully interpreted.
77
More-
over, it is difficult to put much weight on this analysis when a random-
ized study showed negative results.
10 |IRON OVERLOAD AND CHELATION
PRE-TRANSPLANTATION
Chronic red cells transfusion and ineffective erythropoiesis leading to
hepcidin suppression can result in iron overload in patients with
TABLE 8 Summary of publications on pre- and post-transplant
treatments
Reference Method Results
Schroeder
et al.
58
Retrospective study in
pre-transplant MDS
patients
•Upfront allo-
HSCT (n=67)
•Chemotherapy
(n=64)
•HMA (n=34)
5-year NRM 16% (95% CI
9–26), 18% (95% CI
10–29), 15% (95% CI
9–26), respectively;
p=.90
5-year RFS 38% (95% CI
26–49), 41% (95% CI
28–53), 38% (95% CI
20–56), respectively;
p=.926
5-year OS 61% (95% CI
50–75), 50% (95% CI
38–63), 45% (95% CI
27–64), respectively;
p=.116
Potter
et al.
59
Retrospective study in
pre-transplant MDS
patients
•HMA (n=77)
•chemotherapy
(n=132)
3-year NRM 26% (95% CI
14–38), 26% (95% CI
18–35), respectively;
p=.474
3-year RFS 29% (95% CI
16–42), 36% (95% CI
27–46), respectively;
p=.638
3-year OS 42% (95% CI
26–57), 41% (95% CI
31–51), respectively;
p=.274
Liu el at.
60
Meta-analysis study in
pre-transplant MDS
patients (seven
retrospective studies)
•HMA (n=395)
•BSC (n=425)
OS: HR =0.86, 95% CI
0.64–1.15; p=.32
I
2
=0%, p=.86
Oran
et al.
76
Phase III randomized
study in maintenance
post-transplant
AML/MDS patients
•Observation (n=94)
•AZA (n=87)
Median RFS 1.28 years
and 2.07 years,
respectively; p=.43
Median OS 2.56 years
and 2.52 years,
respectively; p=.85
Abbreviations: allo-HSCT, allogeneic hematopoietic stem cell
transplantation; AZA, azacytidine; BSC, best supportive care; CI,
confidence interval; HMA, hypomethylating agents; MDS, myelodysplastic
syndromes; NRM, non-relapse mortality; OS, overall survival; RFS, relapse-
free survival.
332 VITTAYAWACHARIN ET AL.
MDS.
78
It has been shown that secondary iron overload significantly
decreased OS with HR of 1.36 for every 500 ng/ml above serum ferri-
tin threshold at 1000 ng/ml.
79
The inferior OS in MDS patients with
iron overload is primarily associated with increased iron deposition in
major organs, such as heart or liver. Moreover, iron overload may
increase the risk of infectious complications, in particular, invasive
fungal infections.
80–82
In transplant candidates, results from the ALLIVE trial demon-
strated that MRI-derived liver iron content ≥125 μmoL/g and elevated
enhanced labile plasma iron before transplantation were independent
predictors of NRM.
83
Moreover, according to a GITMO study, post-
transplantation MDS patients with transfusion dependency had signif-
icantly poorer OS (HR 1.48; p=.017) and higher NRM (HR 1.68;
p=.024), especially in those with transfusions of more than 20 units
of packed red blood cells or serum ferritin >1000 ng/ml.
84
Improved survival using iron chelation, especially in lower-risk
MDS patients, has been reported in several retrospective or prospec-
tive observational studies. The European MDS registry reported an
improved survival in patients receiving iron chelation therapy com-
pared with patients who did not (HR 0.42; p< .001).
85
A prospective
randomized controlled trial (TELESTO) comparing EFS of lower-risk
MDS patients receiving deferasirox versus placebo showed superior
EFS (3.9 and 3.0 years, HR 0.64; 95% CI 0.42–0.96) in the deferasirox
group.
86
Unlike lower-risk MDS patients, data of iron chelation in higher-
risk MDS or transplant candidates are scarce. A retrospective study in
higher-risk MDS patients with deferasirox showed similar efficacy and
toxicity as reported in the lower-risk group.
87
Regarding the role of iron chelation therapy, the EBMT study
group reported that pre-transplant iron chelation did not lead to an
improved OS; however, early iron reduction with either iron chelator
or phlebotomies before 6 months post-transplantation improved RFS
compared with no iron reduction group (90% and 56%; p=.04).
88
In conclusion, it remains unclear if iron chelation, even in patients
with high ferritin, is associated with improved survival post-transplant.
According to the European Leukemia Network recommendations, iron
chelation could be considered in MDS patients who are considered
candidates for transplantation, yet this is based on low level
evidence.
89
11 |TRANSPLANTATION FOR PATIENTS
WITH THERAPY RELATED MDS
According to the 2016 revision to the WHO classification of myeloid
neoplasms and acute leukemia, t-MDS is categorized in the therapy-
related myeloid neoplasms,
1
which develops after cytotoxic and/or
radiation therapy for solid or hematologic malignancies. Quintas-
Cadama et al. developed a prognostic model for t-MDS using seven
factors influencing the survival, including age ≥65 years, Eastern
Cooperative Oncology Group (ECOG) Performance Status Scale 2–4,
poor risk cytogenetics (7 and/or complex), WHO MDS subtype
RARS or refractory anemia with excess blasts-1/2, hemoglobin <11 g/
dl, platelet count <50 10
9
/dl, and transfusion dependency. This
scoring system divided patients into three groups, good risk (0–2 risk
factors, median OS 34 months, 1-year LFS 96%), intermediate risk
(3–4 risk factors, median OS 12 months, 1-year LFS 84%), and poor
risk (5–7 risk factors, median OS 5 months, 1-year LFS 72%).
90
In a propensity score matched analysis comparing t-MDS with de
novo MDS (d-MDS) by Itonaga et al., patients with t-MDS had similar
3-year CIR (32.8% vs. 33%, respectively; p=.983) but higher 3-year
TRM (30.9% vs. 19%, respectively; p=.005) and worse OS (40%
vs. 50%, respectively; p=.032). In multivariate analysis, four factors
were identified as important to be associated with worse survival,
including age ≥55 years, poor cytogenetic risk group, ECOG 2–4 and
a shorter interval from diagnosis to transplantation less than
8 months.
91
Recently, CIBMTR also published retrospective data on transplant
outcomes for patients with therapy-related myeloid neoplasms. The
1-year and 5-year NRM in t-MDS were 24% and 34%, respectively,
with 1- and 5-year DFS and OS of 37% and 19%, and 50% and 27%
respectively. Lower DFS correlated with increase age (>60 years), his-
tory of autologous HSCT, and very high IPSS-R. Independent factors
for inferior OS were age >60, use of a mismatched MUD and
intermediate- to very high IPSS-R. Relapse of the primary disease was
a main cause of death (46%), and occurred mostly within the first-year
post-transplant.
92
Interestingly, retrospective data from Aldoss and colleagues
showed that there was no difference in 5-year OS after allo-HSCT
between t-MDS and d-MDS (49.9% and 53.9% respectively; p=.61).
Moreover, TP-53 mutation in t-MDS patients did not appear to have a
negative effect on post allo-HSCT OS (HR 1.12; p=.79) or RFS
(HR 1.42; p=.37).
25
In a different retrospective analysis focusing on
the subgroup of t-MDS after autologous transplantation for lym-
phoma, a higher NRM was observed (44% at 3 years) and median OS
after allo-HSCT was only 6.9 months suggesting that these patients
should probably receive only RIC which is associated with lower
NRM. In addition, the use of a mismatched unrelated donor was asso-
ciated with lower survival compared with MRD or MUD after multi-
variable analysis (HR 6.21; p=.007).
93
12 |CONCLUSIONS
Allo-HSCT significantly improves survival in patients with higher-risk
MDS compared with alternative therapies, including for older individ-
uals, and should be considered as a standard of care for these patients
who are otherwise fit for this procedure.
Better prognostic scores have been developed which allow not
only for better selection of patients but also a better understanding of
survival post-transplant based on disease and patient-related factors.
Molecular mutations have been shown to significantly impact the
prognosis of patients with MDS with and without transplantation.
Induction therapy using HMA or ICT may be considered while
waiting for pre-transplant evaluation; however, allo-HSCT should be
performed as soon as possible to avoid disease progression.
VITTAYAWACHARIN ET AL.333
The benefit of post-transplant maintenance therapy has not been
proven and should be considered only as part of a clinical trial.
Haploidentical donor transplants extend transplantation to virtu-
ally all patients with MDS with similar outcomes with HLA-matched
transplants, yet this group of patients has not been included in recent
studies due to a more recent expansion of haploidentical donors for
transplantation. Outcomes of patients with TP53 mutation, especially
when associated with high-risk cytogenetics, remain very poor and
novel approaches to enhance GVL effects are urgently needed. There-
fore, evaluation for allo-HSCT should be considered as the priority in
higher-risk MDS patients, not only in younger fit patients, but also in
older patients with good performance status and lower number of
comorbid conditions.
13 |TAKE HOME MESSAGES
•Allogeneic stem cell transplantation is associated with improved
survival compared with non-transplant treatment options for
patients with MDS, including for older individuals.
•Older patients should receive a reduced-intensity conditioning reg-
imen yet which conditionig regimen provides better disease contol
without excessive treatment-related mortality remains unclear.
•Novel approaches to decrease relapse post-transplant are needed,
especially for patients with TP53 mutations.
FUNDING INFORMATION
None.
CONFLICT OF INTEREST
No potential conflict of interest was reported by the authors.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were cre-
ated or analyzed in this study.
ORCID
Pongthep Vittayawacharin https://orcid.org/0000-0002-1131-
5564
Piyanuch Kongtim https://orcid.org/0000-0003-2130-7645
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How to cite this article: Vittayawacharin P, Kongtim P,
Ciurea SO. Allogeneic stem cell transplantation for patients
with myelodysplastic syndromes. Am J Hematol. 2023;98(2):
322‐337. doi:10.1002/ajh.26763
VITTAYAWACHARIN ET AL.337
