REVIEW

CURRENT
OPINION Haematopoietic stem cell transplantation for
acquired aplastic anaemia
Moya E. Young a, Victoria Potter a, Austin G. Kulasekararaj a,b,
Ghulam J. Mufti a,b, and Judith C. Marsh a,b

Purpose of review
Survival outcomes from haematopoietic stem cell transplantation (HSCT) in severe aplastic anaemia (SAA)
have improved steadily over the past decades, largely reflecting progress in supportive care and
conditioning regimens. Here we review recently published data that highlight the improvements and current
issues.
Recent findings
Human leukocyte antigen (HLA)-matched sibling donor (MSD) HSCT remains the gold standard for SAA
patients younger than 40–50 years, with HLA-matched unrelated donor (MUD) HSCT for second line after
failure to respond to immunosuppressive therapy (IST). The use of alternative donor sources for aplastic
anaemia patients remains limited and problematic, but novel conditioning regimens, particularly in the
haploidentical setting, justify further evaluation. In recent studies when comparing alemtuzumab-based
conditioning with standard antithymocyte globulin conditioning regimens, lower rates of acute and chronic
graft-versus-host disease and better tolerance in older patients are seen.
Summary
Improving outcomes may lead to an expanded frontline HSCT role in the future. In children lacking a MSD,
increasingly MUD HSCT is being considered as first-line treatment and is also being considered more for
young adults. Further research is needed to advance our understanding of the role HSCT has to play in
SAA with particular emphasis on alternative donor sources and identifying optimal conditioning regimens.
Keywords
alemtuzumab, antithymocyte globulin, haematopoietic stem cell transplant, severe aplastic anaemia

INTRODUCTION is also emerging, which is adding further levels of

Aplastic anaemia remains a rare but potentially life-
threatening disorder for which allogeneic haemato-
poietic stem cell transplantation (HSCT) offers
potential cure [1]. In young patients with a human
leukocyte antigen (HLA)-matched sibling, upfront
HSCT is currently the recommended treatment
option [2]. Improvements in donor selection, con-
ditioning protocols, and supportive care along with
advances in understanding of disease biology have
contributed to the increasing success rates of this
&&
procedure [1,3 ]. Indeed, along with these advan-
ces, the number of transplant procedures as a thera-
peutic modality continues to rise year upon year [4].
This has led to much debate about a potential
expanded role for HSCT in older patients with severe
aplastic anaemia (SAA), particularly those who are
refractory to immunosuppressive therapy (IST).
Research, mainly from small-scale studies, looking
at new conditioning regimens and stem cell sources
complexity to the debate. This review discusses the
current position of allogeneic HSCT in adults with
acquired aplastic anaemia and looks at emerging
trends that may impact the future.
INDICATIONS AND DONORS FOR
TRANSPLANT
HSCT in SAA provides an opportunity to generate a
lasting haematological response, minimize relapse
a
Haematology Department, Kings College Hospital and bKings College
London, London, UK
Correspondence to Professor Judith Marsh, Consultant Haematologist,
Department of Haematology, Kings College Hospital, Denmark Hill,
London SE5 9RS, UK. Tel: +44 20 3299 3362; fax: +44 20 3299
3663; e-mail: judith.marsh@nhs.net
Curr Opin Hematol 2013, 20:515–520
DOI:10.1097/MOH.0b013e328365af83

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 Hematopoietic stem cell transplantation
KEY POINTS

MSD HSCT is established first-line management for
SAA patients aged up to 40–50 years.

Improved outcomes for MUD HSCT in aplastic anaemia
are encouraging and may have an increasing role in the
future therapeutic armamentarium of aplastic anaemia.

The encouraging early reports using haploidentical
transplants with novel conditioning protocols, especially
posttransplantation cyclophosphamide, need to be
further explored in aplastic anaemia.

Conditioning protocols using alemtuzumab instead of
ATG provide comparable overall survival and low rates
of chronic GvHD.

The finding of stable mixed chimerism using
alemtuzumab conditioning and the concept of tolerance
is intriguing, and needs further evaluation.
and reduce the risk of clonal evolution to myelo-
&
dysplasia [5 ]. Transplantation as per current guide-
lines is indicated for severe or very severe aplastic
anaemia, and aplastic anaemia either as first-line
therapy or that has failed IST. Once it has been
decided that a patient has an indication for trans-
plantation, the next decision point is determined
by patient age and the availability or otherwise
of a matched sibling donor (MSD) [2]. For SAA
patients less than 40–50 years of age, MSD HSCT
is considered the treatment of choice with reported
5-year overall survival (OS) approaching 80–90%
& & &&
[5 ,6 ,7 ,8]. An inverse relationship between age
and outcome has been recognized by a number of
authors, including studies conducted by both the
European Group for Blood and Marrow Transplan-
tation (EBMT) and the Center for International
Blood and Marrow Transplant Research (CIBMTR)
[9]. Hence for older patients, HSCT is reserved as
second-line treatment in those failing one course of
&
IST with an OS rate around 80% with a MSD [6 ]. As
HSCT outcomes have improved over the past
decade, with advances in supportive care, the use
of alternative conditioning regimens in older
patients and the use of ciclosporin, transplant is
now being considered as frontline treatment by
some centres for patients up to the age of 50 years
&
[6 ]. A 65% OS rate for 23 patients over 40 years of
age was reported retrospectively by the Seattle
group, in those who underwent initial treatment
with MSD HSCT using cyclophosphamide-based
(200 mg/kg) conditioning [10]. A key decision
within this older group of aplastic anaemia patients
with a potential MSD still remains at what stage
to offer HSCT. No long-term survival advantage
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comparing HSCT or IST has been identified for older
patients and it is recognized that mortality rates are
significantly higher in patients more than 40 years
of age compared with those less than 40 [11,12].
A large CIBMTR study of 1307 patients identified
older age at transplant as a negative factor for a
variety of reasons, including the prior use of IST,
poor performance score, increased time between
diagnosis and HSCT (>3 months) and use of a
peripheral blood stem cell (PBSC) graft [9]. Under-
standing of these contributory factors as well as a
thorough assessment of comorbidities is important
to determine whether individual patients who are
more than 50 years of age should be considered
for upfront transplantation. The use of fludara-
bine-based conditioning, with lower dose cyclo-
phosphamide, is now advocated for older patients
(>30 years), as this results in better outcomes
compared with cyclophosphamide 200 mg/kg.
In HLA-matched unrelated donor (MUD) trans-
plants for aplastic anaemia patients, OS is improving
and currently stands at about 75% with higher
&
estimates reported in some studies [13 ]. Current
recommendations are for MUD HSCT to occur only
after failure of one course of IST [2]. An unresolved
question relates to the issue of whether improve-
ments in HLA matching may in future result in a
situation in which young adult patients with a fully
matched donor typed at high resolution may be
& &&
offered upfront transplantation [13 ,14 ,15].
Better HLA matching at the allelic level has
the potential to make an important impact with
mismatched donors adversely affecting outcomes.
A recent EBMT analysis has shown this effect can
be mitigated by the use of a conditioning regime
using fludarabine, cyclophosphamide, antithymo-
cyte globulin (ATG; FCATG) with the addition of
low-dose total body irradiation (TBI; 2 Gy), thus
opening up the option of HSCT to SAA patients
who only have a single HLA antigen mismatched
(7/8 or 9/10) unrelated donor [15]. In our institu-
tion, the current practice is to use low-dose TBI
with fludarabine, low-dose cyclophosphamide and
alemtuzumab (FCC) for single antigen mismatched
donors; for fully matched (MUD) HSCT, we use FCC
conditioning without low-dose TBI.
An additional question in the MUD setting
is whether there is an upper age limit for trans-
plantation to be offered. As discussed below, recent
results report encouraging OS in patients more
than 50, particularly in patients with minimal
comorbidities. As improvements continue to
occur, it is likely that age itself will no longer
remain a contraindication to HSCT, with decisions
being made that consider both age and comor-
&&
bidities [14 ].
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 Haematopoietic stem cell transplant for aplastic anaemia Young et al.
THE ROLE OF ALTERNATIVE DONORS
In those patients lacking an HLA-matched sibling
or unrelated donors who have failed at least one
line of IST, a haploidentical stem cell transplant
(haplo-SCT) or cord blood transplant may be con-
sidered. Increasing interest has been placed in these
potential alternative donor routes over the past
decade. Potential family haploidentical donors are
usually readily available, but their use in SAA has
been limited [16]. Haplo-SCTs are complicated
by high rates of graft-versus-host disease (GvHD),
graft rejection and poor posttransplant immune
reconstruction, all of which are deleterious to SAA
patients who require stable engraftment, and confer
&
no benefit from GvHD [17 ]. A review on 12 ado-
lescent patients, median age 13.5 years (range
3.8–21.7 years), of whom nine had previously
received IST, was recently reported. Haplo-SCT con-
ditioning consisted of fludarabine, cyclophospha-
mide and ATG with six receiving additional low-
dose TBI. Engraftment was achieved in 100%, but
only after three patients had had a second trans-
plant. At median follow-up of 14.3 months (range
4.1–40.7 months), all patients were alive and trans-
fusion-independent while three patients experi-
enced acute GvHD grade II–IV [18]. The Seattle
group established prolonged engraftment in a total
of 31 patients with the use of an intense condition-
ing regimen containing full-dose TBI [19]. More
studies looking at various conditioning protocols
in this setting continue to report data. Haplo-SCT
is feasible in the SAA setting, but progress is needed
to improve OS, prolong engraftment and reduce
GvHD incidence with identification of an optimal
conditioning protocol to achieve these goals, such
as the Baltimore regimen using postgraft cyclophos-
phamide [20].
Experience with umbilical cord blood trans-
plants (UCBTs) is limited in acquired SAA [21].
Peffault de Latour et al. [22] have published
analysis on 71 patients receiving single or double
UCBT in 32 centres with various protocols and
GvHD prophylaxis. With median follow-up of
35 months, estimated OS probability at 3 years
was 38% with incidence of grade 2–4 acute GvHD
of 20%. Loss of engraftment leading to death
occurred in 14 patients. The only factor provid-
ing an OS and engraftment advantage was the
prefreezing total nucleated cell (TNC) dose of
the cord unit when greater than 3.9  107/kg. A
prospective phase II Eurocord-EBMT study is
currently underway to investigate UCBT in the
SAA setting [15].
Recently, haplo-SCT followed by cord transplant
(haplo-cord) has been investigated for SAA to see
whether the addition of the related haplo stem cells
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accelerates bone marrow recovery and improves
long-term disease-free survival. Initial results are
promising [23].
When haplo-SCT or UCBT is contemplated,
all patients must be screened for HLA antibodies
directed against the donor.
DONOR STEM CELL SOURCE
Increasingly, granulocyte-colony stimulating factor
(G-CSF)-mobilized PBSCs have been used as donor
cell source with higher CD34þ cell yields compared
with bone marrow-derived cells. The stem cell dose
infused in SAA patients undergoing HSCT can
impact on the risk of graft failure. A bone marrow
CD34þ cell dose of less than 2.0  106/kg signifi-
cantly increases this likelihood. Bone marrow har-
vests can on occasion provide poor yields and this in
part has led to the increased use of PBSCs. The
impact of CD34þ cell dose on survival and GvHD
rates has yet to be determined [24,25].
An important issue relates to whether PBSC or
bone marrow is the preferred stem cell source for
patients with aplastic anaemia. It is generally agreed
that the use of PBSC results in higher rates of GvHD.
Several retrospective analyses have reported a higher
incidence of GvHD in PBSC-derived grafts compared
with bone marrow-derived cells in all age groups. A
recent large analysis by the aplastic anaemia work-
ing group of the EBMT of 1886 transplants per-
formed between 1999 and 2009 sought to address
this issue in the MSD setting. As well as an increase
in chronic GvHD, a survival disadvantage across all
age groups was noted for recipients of PBSCs, lead-
ing the authors to conclude that bone marrow
should be considered the preferred stem cell source
for MSD HSCT [26]. A smaller study of 296 patients
(225 bone marrow, 71 PBPC) from the CIBMTR
reported on outcomes in the unrelated donor set-
ting. Haematological recovery was similar between
the groups. Grade II–IV acute GvHD was higher in
the PBSC group, 48 vs. 31%, respectively (P ¼ 0.02),
whereas chronic GvHD did not differ significantly.
The risk of mortality, independent of age, was
higher after PBSC grafting (hazard ratio 1.4,
P ¼ 0.04), again leading to the recommendation
that bone marrow should be the preferred graft
[27]. Of note, engraftment was significantly faster
(P <0.0001) and more frequent in the PBSC group
when compared with bone marrow group [28].
Important to consider when reviewing these studies
are the other issues that also affect outcome, such as
older age, time from diagnosis to HSCT and the use
of ATG/T-depletion in the conditioning protocol.
An additional potentially unrecognized issue is that
of centre experience in the bone marrow harvest
www.co-hematology.com 517
 Hematopoietic stem cell transplantation
procedure, which has decreased with the increased
use of PBSCs for transplants across all indications.
Centres that lack adequate experience have the
potential to lead to inadequate stem cell yields,
which may compromise outcomes. Although these
retrospective analyses yield important insights, it is
likely that in order to adequately answer these ques-
tions, prospective trials are required.
CONDITIONING REGIMENS AND
TOLERANCE
Unlike malignant disease, any presence of GvHD
in SAA transplant patients has been shown to be
detrimental to long-term outcome. Historically, in
an attempt to improve engraftment, TBI-based
regimens were used; however, this increased the risk
of GvHD and other complications including pneu-
monitis and secondary malignancies. Therefore,
ATG combinations have become the preferred
choice as engraftment is supported while GvHD
reduced in the setting of both MSD and MUD HSCTs
& & &&
[5 ,6 ,7 ,10]. Adding fludarabine reduces the risk of
rejection in heavily transfused or older patients [29].
A popular regimen combining ATG with cyclophos-
phamide, fludarabine and with or without low-dose
TBI showed OS for MUD HSCT was improved. How-
ever, acute GvHD rate was 18%, whereas chronic
GvHD was as high as 50% when low-dose TBI was
used [15]. In recent years, alemtuzumab-based regi-
mens, notably fludarabine, cyclophosphamide and
alemtuzumab (FCC) have been developed and offer
&&
promising results. Marsh et al. [14 ] demonstrated a
low incidence of acute GvHD of 13.7% and chronic
GvHD of 4%, with an impressive 2-year OS of 95 and
83% for MSD and unrelated donor HSCT, respec-
tively. The incidence of graft rejection for MUD of
14.5% is comparable to an EBMT study of ATG-based
regimens, including TBI, with a rate of 17%. These
data have since been corroborated with further
studies. In fully matched unrelated donor HSCT
regimens using alemtuzumab, TBI is not required
to aid engraftment, unlike ATG-based regimens.
Furthermore, methotrexate is not required as post-
graft immunosuppression, instead ciclosporin alone
is sufficient. Alemtuzumab-based regimens offer the
potential of excellent survival rates, engraftment
rates and low rates of GvHD with tolerable side-
effects even in MUD HSCT.
The British Society for Blood and Marrow Trans-
plantation (BSBMT) performed a retrospective
multicentre study of 159 SAA patients comparing
ATG-based regimens (n ¼ 55) to those with alemtu-
zumab (n ¼ 103). There was no difference between
the two groups with respect to 1-year OS (84 vs. 91%,
respectively, P ¼ 0.1578). Alemtuzumab, however,
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was shown to have preferential OS outcome in
the MUD setting, but there was no significant differ-
ence in MSD HSCTs. Alemtuzumab resulted in a
lower risk of chronic GvHD compared with ATG
[30].
In alemtuzumab regimens used in SAA, mixed
donor chimerism is frequently seen. This may
signify that a state of tolerance, defined by the
finding of stable mixed T-cell chimerism, full donor
myeloid chimerism with the absence of chronic
GvHD after HSCT and on withdrawal of IST, appears
to be established. This in turn is associated with
excellent survival. Further studies of immune recon-
stitution and the role T-cell populations play after
&
HSCT will provide important future insights [31 ].
Fludarabine–alemtuzumab-based conditioning
protocols have favourable outcomes and good
tolerability in the older patient with lower rates of
infections and GvHD, and are indicated for MSD
HSCT patients over 30 years of age and for all MUD
HSCTs. Conventional ATG–cyclophosphamide
conditioning regimens for MSD HSCT are now used
in patients aged less than 30 years because OS for
older patients is poor. This is likely a reflection of
higher incidence of GvHD and organ toxicity.
Although numbers were small, a review of patients
aged 50–62 receiving MSD HSCT with FCC con-
ditioning had a 2-year OS of 71%. In this study,
the significant impact of the pretransplant haema-
topoietic cell transplantation-comorbidity index
(HCT-CI) on survival was highlighted: a HCT-CI
score of 2 or more had a worse OS outcome of only
&& &&
42% [14 ]. Table 1 [14 ,15,29,32–34] lists the
recent studies of ATG and alemtuzumab-based con-
ditioning for MUD HSCT in SAA.
LONG-TERM OUTCOMES
Due to improved survival and increasing numbers of
transplants performed for SAA, a growing posttrans-
plant population exists however, there are limited
data published with regard to long-term compli-
cations. A recent large analysis by the CIBMTR
reviewed long-term outcomes of HSCT in 1718
(1176 MSD; 542 MUD; median age 20) acquired
SAA patients. The median follow-up was 70 months
for MSD and 67 for MUD transplants. At 1 year, OS
was 76%. Although at least one late effect was noted
in 6% and 13% of MSD and MUD HSCT, respec-
tively, multiple late effects were only seen in 1% and
2% of patients. For survivors of MSD HSCT, the
cumulative incidence of developing late effects
was low at less than 3% and importantly did not
increase over time. This was in contrast to recipients
of MUD wherein the cumulative incidence of devel-
oping several late effects exceeded 3% by 5 years
Volume 20
Number 6
November 2013
 Haematopoietic stem cell transplant for aplastic anaemia Young et al.

Table 1. Published results from recent studies of antithymocyte globulin and alemtuzumab-based conditioning
haematopoietic stem cell transplantation in human leukocyte antigen-matched unrelated donor severe aplastic
anaemia
Authors N Median age (years) Conditioning Graft failure (%) GvHD Overall survival

Bacigalupo et al. [15] 100 20 Cy-ATG-TBI 17 Acute II–IV 18% 75% at 5 years
Flu-Cy-ATG-TBI Chronic 27% (no TBI),
50% (TBI)
Kang et al. [32] 28 13 Flu-Cy-ATG 0 Acute II–IV 46% 68% at 3 years
Chronic 35%
Marsh et al. [14 ] 50 35 Flu-Cy-Alem 12 Acute I–II 13.4% 83% at 2 years
&&

III–IV 0%
Chronic 8%
Novitzky et al. [29] 30 19 Flu-Cy-Alem 10 Acute 0% 100% at 1939 days
Kanda et al. [33] 15 34 Flu-Cy-Alem 8.3 Acute II–IV 0% 83.3% at 1 year
Samarasinghe et al. [34] 44 8.1 Flu-Cy-Alem 0 Acute I–II 31.8% 95% at 5 years
Chronic 6.8%

Alem, alemtuzumab; ATG, antithymocyte globulin; Cy, cyclophosphamide; Flu, fludarabine; GvHD, graft-versus-host disease; N, number of study patients; TBI,
total body irradiation.

with gonadal dysfunction, growth disturbance, matched donors. New preliminary data are appear-
avascular necrosis, hypothyroidism and cataracts ing, but larger studies are required.
occurring most commonly [35]. Rates of malignancy
are comparable to those seen in malignant disorder Acknowledgements
HSCT individuals [36]. Although the authors con- None.
cede that the follow-up in the aforementioned study
was relatively short, and hence effects that occur Conflicts of interest
with a long lag time may have been overlooked, the J.M. received research funding from Genzyme in 2010,
analysis does highlight some more common long- and did consultancy work for Sanofi in October 2012 and
term complications. Important for all long-term Pfizer in January 2013.
survivors is continued surveillance for long-term
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& of special interest
&& of outstanding interest

CONCLUSION
OS in SAA has improved significantly over the past
decades due to advances in HSCT and IST. Due to the
rare nature of the disease, patient numbers in the
majority of studies are small and many studies are
retrospective. Many debates still exist concerning
the optimal conditioning regimen, FCATG vs. FCC,
the upper age limit for HSCT in SAA patients, and
stem cell dose and source. MSD HSCT continues to
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Volume 20
Number 6
November 2013