Cotransplantation of haploidentical
hematopoietic and umbilical cord
mesenchymal stem cells for severe aplastic
anemia: Successful engraftment and
Wu Yameia,1, Cao Yongbina,1, Li Xiaohonga, Xu Lixina, Wang Zhihonga,
Liu Peia, Yan Peia, Liu Zhouyanga, Wang Jinga, Jiang Shuanga,
Wu Xiaoxionga,⁎, Gao Chunjib, Da Wanmingb, Han Zhongchaoc
aDepartment of Hematology, The First Affiliated Hospital, Chinese PLA General Hospital, Beijing 100048, China
bDepartment of Hematology, Chinese PLA General Hospital, Beijing 100853, China
cTEDA Research Center of Life Science and Technology, State Key Laboratory of Experimental Hematology,
Institute of Hematology, Tianjin 300020, China
Received 24 March 2012; received in revised form 26 September 2013; accepted 1 October 2013
Available online 10 October 2013
failure and severe graft-versus-host disease (GVHD). Mesenchymal stromal cells (MSCs) have been shown to support in vivo
normal hematopoiesis and to display potent immunesuppressive effects. We cotransplanted the culture-expanded third-party
donor-derived umbilical cord MSCs (UC-MSCs) in 21 young people with severe aplastic anemia (SAA) undergoing haplo-HSCT
without T-cell-depleted. We observed that all patients had sustained hematopoietic engraftment without any adverse UC-MSC
infusion-related events. Furthermore, we did not observe any increase in severe aGVHD. These data suggest that UC-MSCs,
possibly thanks to their potent immunosuppressive effect on allo-reactive host T lymphocytes escaping the preparative
regimen, reduce the risk of graft failure and severe GVHD in haplo-HSCT.
© 2013 The Authors. Published by Elsevier B.V.
Open access under the CC BY-NC-ND license.
Haploidentical hematopoietic stem-cell transplantation (haplo-HSCT) is associated with an increased risk of graft
Allogeneic hematopoietic stem cell transplantation (HSCT) is
an effective therapeutic modality for young patients with
severe aplastic anemia (SAA) who have an immediate HLA-
identical donor. However, less than 30% of patients who
require allogeneic HSCT have a human leukocyte antigen
(HLA)-compatible sibling. In China, searching for HLA-matched
donors is usually unsuccessful because no siblings are available
for almost all young people. Fortunately, haplo-identical
⁎ Corresponding author at: Department of Hematology, The
First Affiliated Hospital, Chinese PLA General Hospital, 51
FuCheng Road, Beijing 100048, China. Fax: +86 10 66848181.
E-mail address: email@example.com (X. Wu).
1Wu Yamei and Cao Yongbin contributed equally to this study
and should be considered as co-first authors.
1873-5061 © 2013 The Authors. Published by Elsevier B.V.
Available online at www.sciencedirect.com
Stem Cell Research (2014) 12, 132–138
Open access under the CC BY-NC-ND license.
hematopoietic stem cell transplantation (haplo-HSCT) has
come into clinical use to treat hematologic malignancies and
the protocols have been greatly improved during the last
decade (Guo et al., 2009; Lazarus et al., 2005). However,
the results of haplo-HSCT in patients with SAA have been
disappointing, due to high risk of treatment-related mortality
engraftment failure, and acute and chronic graft-versus-host
disease (aGVHD, cGVHD) (Woodard et al., 2004; Lazarus and
Koc, 2001; Tsutsumi et al., 2004; Tabbara et al., 2002).
Mesenchymal stem cells (MSCs) are a heterogeneous subset
of multipotent stromal stem cells, which express low levels of
class I, but not class II, histocompatibility antigens and are not
al., 2008; D.P. Lu et al., 2006; L.L. Lu et al., 2006). MSCs have
also been shown to suppress primary and ongoing mixed
lymphocyte reactions (Klyushnenkova et al., 1998; Di Nicola
et al., 2002; Ball et al., 2007). MSCs can be isolated from many
adult tissues, including bone marrow (BM), periosteum, adipose
tissue, fetal liver, cord blood and umbilical cord (UC) tissues
(In't Anker et al., 2003; Lee et al., 2004; Romanov et al., 2003).
Recently, some experimental and clinical data demonstrated
that BM-MSCs can support hematopoiesis, enhance the
engraftment of HSCs, and reduce the incidence of GVHD
following HSCT (Guo et al., 2009; Lazarus et al., 2005).
However, the aspiration of BM involves invasive procedures,
and the frequency and differentiation potential of BM-MSCs
decrease significantly with age (D.P. Lu et al., 2006; L.L. Lu
et al., 2006). Lu LL et al. have shown that a large number of
MSCs can be easily isolated from the UC and collected using
an accessible and painless procedure (D.P. Lu et al., 2006;
L.L. Lu et al., 2006). Our recent data demonstrated that the
modified haplo-HSCT combined with third-party donor-derived
UC-MSCs for 50 patients with refractory/relapsed hematologic
malignancy was not only safe and feasible but also effective for
the improvement of donor engraftment and the reducing of
severe GVHD (Wu et al., 2013). However, it is still unknown
with SAA can reduce graft failure.
Herein, we report the results of our clinical trial of haplo-
HSCT with modified conditioning that was designed primarily to
examine the safety and feasibility of the cotransplantation of
HSCs in SAA patients. We further investigated the rates and
kinetics of hematopoietic engraftment and the incidence and
severity of GVHD.
Engraftment and chimerisms
In Table 1, the median hematopoietic cell doses infused were
9.28 × 108mononuclear cells (range, 6.30–13.18 × 108/kg) and
3.79 × 106CD34+cells (range, 1.96–10.20 × 106/kg). Data for
all patients who survived at least 30 days after transplantation
Overall, the median time to achieve neutrophil engraftment
(absolute neutrophil count ≥0.50 × 109/L) was 12.0 days
(range, 8.0–21.0 days). Overall, the median time to achieve
platelet engraftment ≥20 × 109/L was 14.0 days (range,
10.0–23.0 days). Delayed platelet recovery (N30 days) was
not observed in any of the 21 patients. All patients achieved
full donor chimerism (FDC) (Table 2).
Table 2 indicates the incidence and severity of GVHD. Overall,
12 of 21(57.1%) patients experienced aGVHD between 20 and
4(19.0%) with grade II, 4 (19.0%) with grade III and 1 (4.8%)
with grade IV aGVHD. The other 9 patients had no aGVHD. Ten
of 20 (50.0%) evaluable patients who survived at least 90 days
after transplantation experienced cGVHD; cGVHD was limited
in 7 patients (35.0%) and extensive in 3 patients (15.0%).
Upon follow-up for 2.5 to 78 months, 17 of the 21 (80.9%)
patients were alive. As shown in Fig. 1, the probabilities of
2-year disease-/progression-free survival were 74.1% in
the 21 patients. No patients experienced disease relapse or
progression. Fourpatientsdied; three patientsdiedasa result
of infection, and the other patients died as a result of GVHD.
Clinical safety outcomes
As anticipated for the HSC transplant recipients, all 21
patients experienced at least 1 adverse event during the
study period, and 16 of 21 (76.2%) patients developed at
least one grade IV adverse event (Table 3). Only 4 patients
(19.0%) demonstrated adverse events that were considered
treatment related, such as GVHD, organ failure, or others
(i.e., possibly, probably, or definitely). However, no patients
experienced infusional toxicity during the UC-MSC infusion.
Graft failure and rejection for patients with acquired
SAA remains as one of the important and life-threatening
complications, especially in haplo-HSCT (Wagner et al., 1996;
Passweg et al., 2006). The EBMT showed that for patients
receiving HLA-identical sibling grafts, the rate of graft failure
several decades, various transplant strategies have been
introduced to decrease graft failure, with mixed success
(Wang et al., 2009; Fang et al., 2008, 2009; Wagner et al.,
1996; Passweg et al., 2006; Storb et al., 1986; DE Medeiros
study-specified modified conditioning regimens without T-cell
depletion for HLA-haplo relative HSCT. All patients with 2–3
mismatched loci achieved sustained full donor engraftment
and prompt hematopoietic recovery. Results suggested
that the modified conditioning regimen without high-dose
immunosuppressive agents was sufficient toachieve sustained
donor engraftment in which the third-party donor-derived
UC-MSCs may play an important role.
In allogeneic stem cell transplantation, MSC may be used
for GVHD prophylaxis and treatment of severe aGVHD (Wang
et al., 2009; Fang et al., 2008, 2009; Le Blanc et al., 2004;
Lazarus and Koc, 2001). Le Blanc demonstrated that the
infusion of MSCs was an effective therapy for patients with
133Cotransplantation for severe aplastic anemia
steroid-resistant GVHD in a phase II clinical trial (Le Blanc
et al., 2008). Lu et al. showed that UC-MSCs do not express
the immune costimulatory molecules or HLA-DR and express
from January 2006 to December 2007. Five patients aged 14
to 25 with 1–2 mismatched loci received haplo-HSCT with
the same conditioning regimen and GVHD prophylaxis except
UC-MSCs. Even though no patient had graft failure, one patient
had mixed chimerisms (MC). The incidences for grades II to IV
and III/IV aGVHD were up to 60.0% and 40%, respectively. At
the same time, extensive cGVHD occurred in 1 patient (33.3%)
of 3 evaluable patients who survived at least 90 days after
transplantation. The most disappointing results were that only
2 (40.0%) patients were alive in the following 24 months. In
the present trial, we intended for GVHD prophylaxis to consist
of cyclosporine (CsA), mycophenolate mofetil (MMF), rabbit
anti-human T-lymphocyte immunoglobulin (ATG), anti-CD25
antibody (CD25Ab) and UC-MSCs, and we did not observe an
increase in severe aGVHD. Many studies have shown that the
64% and from 12% to 26%, respectively. Extensive cGVHD rates
range from 30% to 46% (Bensinger et al., 2001; Couban et al.,
2002). Grade III/IV aGVHD rates (23.8%) and cGVHD (47.6%)
rates identified in the trial fall within these ranges and would
be a little better than the above mentioned. Similar results
were also observed in our recent studies in 50 patients with
refractory/relapsed hematologic malignancy of haploidentical
HSCT (Wu et al., 2013). All of these results suggest that
the infusion of third-party donor-derived UC-MSCs may play
a considerable role in the lessening of severe GVHD. A
randomized double-blind clinical trial evaluating the use of
third-party donor-derived UC-MSC infusion for the prevention
the efficacy of this treatment regimen.
In comparison with other reports (Wang et al., 2009; Fang
et al., 2008, 2009; D.P. Lu et al., 2006; L.L. Lu et al., 2006)
in which large amounts (over 1 × 106/kg) of MSCs were usually
infused intravenously, we administered 5 × 105cells/kg of UC-
with milder GVHD and stable engraftment. Our results indicate
that this dose of UC-MSCs retained an effective role. Further-
the administration of donor UC-MSCs into all patients.
In conclusion, our data demonstrate that the modified
haplo-HSCT combined with third-party donor-derived UC-MSCs
for patients with SAA was not only safe but also effective for
the improvement of donor engraftment and the lessening of
feasible option for the salvage treatment of acquired SAA.
Table 1 Demographic and transplant characteristics of patients and donors.
Case Sex/AgeStatus prior to
SAA & PNHg,#
SAA & PNHg,#
Donor/Age HLA mismatchABO pairs
MNC 108/kgCd34+ 106/kg
A B DR
A B DR
A B DR
A B DR
A B DR
A B DR
A B DR
A B DR
A B DR
A B DR
A B DR
A B DR
MNC, mononuclear cells; F, female; M, male; HLA, human leukocyte antigen; SAA, severe aplastic anemia; VSAA, very severe aplastic
anemia; PNH, paroxysmal nocturnal hemoglobinuria; ATG, rabbit anti-human T-lymphocyte immunoglobulin; D, donor; R, recipient.
aFirst graft failure.
bRelapse after ATG.
cViral hepatitis before aplastic anemia.
dThyroid carcinoma before aplastic anemia.
eViral encephalitis before aplastic anemia.
fMore than 15 units red blood cells were transfused.
gMore than 25 units red blood cells were transfused.
⁎ Conditioning regimen 1.
#Conditioning regimen 2.
134Y. Wu et al.
Patients and methods
Patients and study design
Twenty-one patients with SAA aged4 to 31 (median 18 years),
our center from January 2007 to June 2013. Detailed
information about the patients and preparation of donors
were listed Supplementary materials 1 and in Table 4
(Camitta et al., 1979). The clinical protocol and consent
forms were approved by the institutional review board
for human investigation. Patients or their legal guardians
provided written informed consent for their inclusion in the
HLA compatibility was determined by low-resolution DNA
techniques for HLA-A and B loci and high-resolution DNA
techniques for HLA-DRB1 (Mickelson et al., 1993; Petersdorf
et al., 1991).
UC-MSCs were purchased from the National Engineering
Research Center of Cell Products, State Key Laboratory of
Experimental Hematology.Theimmunophenotypeof UC-MSCs
Table 2 The outcome of transplantations in 21 patients.
0.5 × 109/L (D)
20 × 109/L (D)
Dead 5, infection
Dead 6, GVHD
Dead 13, infection
Dead 3, infection
ANC, absolute neutrophil count; PLT, platelets; aGVHD, acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease; Ext,
extensive; Lim, limited; D, day; M, months.
M1:the first month after transplantation.
aOrgan was affected by GVHD: liver.
bOrgan was affected by GVHD: skin.
cOrgan was affected by GVHD: intestinal.
dOrgan was affected by GVHD: lung.
eOrgan was affected by GVHD: eye.
Survival Distribution Function
PFS after Transplantation
transplantation. The probability of 2-year PFS for all patients
135Cotransplantation for severe aplastic anemia
was listed in Supplementary materials 2 (D.P. Lu et al., 2006;
L.L. Lu et al., 2006).
The modified conditioning regimen was based on our
previous protocol for HLA-identical sibling HSCT. Conditioning
procedures included 1 of 2 regimens: (1) fludarabine (Flu)
30 mg/m2/day (days −5 to −2), cyclophosphamide (Cy)
600 mg/m2/day (days −5 to −2) and ATG 5 mg/kg/day (days
−4 to −1) (Fig. 2A); or for SAA & PNH only (2) busulfan (Bu)
0.6 mg/Kg/6 h (days −8 to −5), Cy 1.8 g/m2/day (days −4,
−3), and ATG 5 mg/kg/day (days −4 to −1) (Fig. 2B) (Wang
et al., 2009; Fang et al., 2008, 2009).
Allogeneic HSC infusion
At the start of the study, BM and peripheral blood stem cells
(PBSCs) (the percentages of BM and PBSCs were same) were
both elected as the source of cellular rescue. Supplementary
a central venous catheter on day 0 and day 1 respectively.
The planned UC-MSC dosing scheme was 5.0 × 105/kg in all
patients. Before a planned UC-MSC infusion, the cells were
shipped in liquid nitrogen containers to our transplantation
center. BM infusions were performed 4 h after the completion
of UC-MSC infusion.
Prophylaxis and treatment of GVHD
GVHD prophylaxis consisted of intravenous CsA 3 mg/kg/day
in divided doses beginning the day before transplantation
(day −5) and was continued thereafter. The oral MMF dose
was 20 mg/kg/day from day −1 and was tapered off after
100 days if no aGVHD was observed. Rabbit ATG (Fresenius
AG, Oberursel, Germany) was administered intravenously at
for all patients versus UC-MSC dose.
Summary of adverse and severe adverse events
Variable Total (N = 9)
≥1 adverse event
≥1 severe adverse event
Fatal severe adverse event
Highest NCI grade or severity
At each level of summation (except for the row for ≥1 adverse
event), the patients who reported more than 1 event were
counted only once.
Data are the number of patients.
⁎ Not related indicates an unrelated or unlikely relationship;
related indicates a possible, probable, or definite relationship.
-5-4-3 -2 -10 +1 +4 +30+100
Flu+CTX BMSC PBSC
ATG MSC CD25Ab
-8 -7-6 -5 -4-3 -2 -10 +1 +4+30 +100
ATG MSC CD25Ab
BU CTXBMSC PBSC
to −2), cyclophosphamide (Cy) 600 mg/m2/day (days −5 to −2) and ATG 5 mg/kg/day (days −4 to −1); or for SAA & PNH only
(B) busulfan (Bu) 0.6 mg/Kg/6 h (days −8 to −5), Cy 1.8 g/m2/day (days −4, −3), and ATG 5 mg/kg/day (days −4 to −1). ATG, rabbit
anti-human T-lymphocyte immunoglobulin; CD25Ab, anti-CD25 antibody; MMF, mycophenolate mofetil; CsA, cyclosprin A.
Sketch of conditioning procedures. Conditioning included 1 of 2 regimens: (A) fludarabine (Flu) 30 mg/m2/day (days −5
136Y. Wu et al.
CD25Ab (Basiliximab, Novartis Pharma Stein AG, Switzerland)
was administered intravenously at a dose of 0.5 mg/kg/day
only on day 4 after HSCT. Patients were advanced to oral
cyclosporine as tolerated. In the absence of GVHD, the oral
cyclosporine dose was reduced weekly by approximately 5%
beginning on or near 6 months, and therapy was usually
discontinued by one year after transplantation. Acute and
Engraftment, toxicity grading, GVHD grading and
infusions (designated as day 0). Neutrophil and platelet
engraftment and hematopoietic chimerism evaluation have
been described in supplementary materials 4. Toxic effects
were graded using the National Cancer Institute Common
Toxicity Criteria for Adverse Events (CTCAE version 4.0). Acute
and chronic GVHD was defined and graded as Supplementary
materials 5 (Storb et al., 1986; Atkinson et al., 1989). Relapse
was defined as the recurrence of disease. Death in the absence
of persistent relapse was categorized as nonrelapse mortality.
All of supportive cares were listed in the Supplementary
Appendix A. Supplementary data
Supplementary data to this article can be found online at
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SAA, severe aplastic anemia; VSAA, very severe aplastic anemia;
PNH, paroxysmal nocturnal hemoglobinuria; Y, year; M, months.
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