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Haploidentical Hematopoietic Stem Cell Transplantation for Hematological Malignancies
Xiao-Jun Huang M.D. Ph.D.Peking University Institute of Hematology,
Peking University People’s Hospital &Beijing Key Laboratory of HSCT,
Beijing, P.R.China
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1
EducationClinic
Research
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The Cumulative Hematopoietic Stem Cell Transplantation (HSCT) Cases of PUIH
PUIHThe Largest HSCT center in AsiaNow >400 cases of HSCT per yearNow >60% Allo-HSCT cases are Unmanipulated Haploidentical HSCT
24%24%
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• Current Clinical Results
• Strategy to Improve the Clinical Results
Haploidentical Hematopoietic Stem Cell Transplantation for Hematological Malignancies
11
• In vitro T-cell-depleted HSCT
22• Non-Myeloablative Haploidentical HSCT
33• Unmanipulated Myeloablative
Haploidentical HSCT
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GIAC protocol
• G: donor treatment with rhG-CSF
• I: intensified immunological suppression
• A: anti-human thymocyte immunoglobulin (ATG)
for the prevention of GVHD
• C: combination of G-PB and G-BM
Huang XJ, et al. Blood, 2006, 107(8):3065-3073Huang XJ, et al. Annals of Medicine, 2008, 40,444-455Huang XJ, et al. Clin Cancer Res. 2009;15:4777-4783Huang XJ, et al. BBMT. 2011 Jun;17(6):821-30.
3. Unmanipulated Haploidentical HSCT
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Effects of G-CSF on Bone Marrow in Healthy Donors
HuangXJ, et al. Clin Transplant 2011: 25: 13–23
3. Unmanipulated Haploidentical HSCT
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Immunoregulatroy Effects after G-CSF Administration to Healthy Donors
Huang XJ, et al. Biol Blood Marrow Transplant.2011;17(2):197-204
3. Unmanipulated Haploidentical HSCT
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400.00300.00200.00100.000.00
Days posttransplant
1.0
0.8
0.6
0.4
0.2
0.0Pro
babi
lity
of e
ngra
ftm
ent (%
)
-censored小于中位值
-censored大于等于中位值
小于中位值
大于等于中位值CD34 ? ?二分 量
400.00300.00200.00100.000.00
Days posttransplant
1.0
0.8
0.6
0.4
0.2
0.0Pro
babi
lity
of e
ngra
ftm
ent (%
)
-censored小于中位值
-censored大于等于中位值
小于中位值
大于等于中位值CD34 ? ?二分 量
Engraftment
Huang XJ, et al. Biol Blood Marrow Transplant,2009, 15(5):632-8
n=348
400.00300.00200.00100.000.00
Day posttransplant
1.0
0.8
0.6
0.4
0.2
0.0Pro
babi
lity
of e
ngra
ftm
ent (%
)
? -censored展期
-censored早期
? 展期
早期? ? ?移植 的疾病
400.00300.00200.00100.000.00
Day posttransplant
1.0
0.8
0.6
0.4
0.2
0.0Pro
babi
lity
of e
ngra
ftm
ent (%
)
? -censored展期
-censored早期
? 展期
早期? ? ?移植 的疾病
P=0.008
n=348
CD34+ cells≥2.19×106/kg
CD34+ cells<2.19×106/kg
P<0.0001
Early stageAdvanced stage
3. Unmanipulated Haploidentical HSCT
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Characteristics of the Allo-Grafts
Summary Statistics
TNC108/kg
CD34+×106/kg
CD3+×108/kg
CD4+×107/kg
CD8+×107/kg
CFU-GM×105/kg
BMRange 1.2 ~ 8.3 0.2 ~ 8.8 0.1 ~ 1.1 0.4 ~ 7.3 0.3 ~ 3.7 1.3~9.4
Median 3.53 1.39 0.20 1.10 1.08 2.62
PBRange 1.9 ~ 9.2 0.6 ~ 6.6 0.6 ~ 6.6 1.9 ~ 39.0 2.9 ~ 29.7 1.4~10.5
Median 4.02 1.58 1.46 8.76 7.01 3.03
TRange 5.2~14.2 0.8 ~ 13.4 0.8 ~ 6.7 3.3~39.6 3.7~29.6 2.2 ~ 19.9
Median 7.56 2.65 1.77 10.39 7.87 5.21
Huang XJ, et al. Bone Marrow Transplant, 2006, 38:291
3. Unmanipulated Haploidentical HSCT
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Huang XJ, et al. Biol Blood Marrow Transplant 2009, 15(2)Huang XJ, et al. Biol Blood Marrow Transplant 2011; 17(6)
Cumulative incidence of aGVHDafter HLA-mismatched allo-HSCT
Haplo=81
Identical=36
P=0.11
3. Unmanipulated Haploidentical HSCT
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Probability of aGVHD with locus disparity
Huang XJ, et al. Bone Marrow Transplant. 2006;38(4):291-7.
3. Unmanipulated Haploidentical HSCT
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DFS & OS compared with HLA Matched Donor
Huang XJ, et al. Blood, 2006, 107(8):3065-3073
3. Unmanipulated Haploidentical HSCT
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Relapse compared with Unrelated Donor ( URD)
Huang XJ, et al. Clin Cancer Res, 2009, 15:4777-4783
PMRD=219
URD=78
PMRD=160
URD=60
3. Unmanipulated Haploidentical HSCT
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Relapse compared with Identical Sibling ( ISD)
HuangXJ, et al. Biol Blood Marrow Transplant. 2011;17(6)
Haplo=81
Identical=36
3. Unmanipulated Haploidentical HSCT
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OS & DFS compared with ISD
PMRD=81
ISD=36P = 0.048 P = 0.029
HuangXJ, et al. Biol Blood Marrow Transplant. 2011;17(6)
Haplo=81
Identical=36
3. Unmanipulated Haploidentical HSCT
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Superior Graft-versus-Leukemia effect
HaploidenticalHLA-identical
sibling
High risk acute leukemia
HuangXJ, et al. Biol Blood Marrow Transplant. 2011 ;17(6):821-30
3. Unmanipulated Haploidentical HSCT
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No. of Haploidentical HSCT accumulated in PUIH
PUIH data
3. Unmanipulated Haploidentical HSCT
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The changing of Composition of Haploidentical allo-HSCT in PUIH from 2007 to 2009
PUIH data
3. Unmanipulated Haploidentical HSCT
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Studies on HLA-mismatched/haploidentical stem cell transplantation (GIAC)
Patients (n) Disease Conditioning
GVHDprophylaxis
aGHVD cGVHD TRM Relapse LFS Reference
35 AML/ALL/
CML/DLBCL/ ATL
Standard intensity±TBI
Tacrolimus based 56% 19% 11 pt 9 pt 40% Ichinohe et
al. (2004)
171 ALL/AML/CML/MDS
Bu/Cy/Ara-C/MeCCNU+
CsA/MTX/MMF 55% 21.3% 19% SR @
2yrs SR 12% SR 68% @ 2yrs
Huang et al. (2006)
135 ALL/AML/CML/MDS
Bu/Cy/Ara-C/MeCCNU+ATG
CsA/MTX/MMF
(II-IV) 40% 55% 22% 18% 64% @
yrs Lu et al. (2006)
68 AML/ALL/CML/MDS/ TBI/Cy/Flu Cy/MMF/ (II-IV) 5% * 4% @ 100
days 51% @ 1 yr 34% @ 1yr
Luznik et al. (2008)
29 AML/ALL/CML/NHL/
Flu/Mel/OKT3/thiotepa
CD3/CD19 depletion
(II-IV) 48% 3 pt 20% @ 100
days 12 pt 35% @ 1yr
Bethge et al. (2008)
42 AML/ALL/CML Bu/Cy/Ara-C/
MeCCNU+ATG
CsA/MTX/MMF 57.2% 27.2% 20.4±6.5% @
1yr 21.43% 57.3±8% @ 3yrs
Liu et al. (2008)
93 CML Bu/Cy/Ara-C/MeCCNU+
CsA/MTX/MMF 64.25% 27.16% 28.3% @ 1yr CP1 3.77% 76.5% @
1yr Huang et al.
(2008)
45 AML/ALL/CML/NHL TBI/Cy/Ara-C/ATG CsA/MTX/
MMF/ (II-IV) 9 pt 3 pt 11 pt 24 pt Wang et al. (2009)
46 AML/CML/ALL TBI/Cy/Ara-C/ATG CsA/MTX/MMF (I-II) 10.9% 8.7% @ 2yrs 23.9% @
2yr 70.6% @
2yrs Chen et al.
(2009)
250 AML/ALL Bu/Cy/Ara-C/
MeCCNU+ ATG CsA/MTX/MMF 45.8% 31.3% AML 11.9%
@ 3yrs AML 19.4%
@ 3yrs AML70.7
%3yrs Huang et al.
(2009)
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Composition of HSCT Donor Types in 24 Transplant Units in China
PUIH collected
Mis % 29.9% 30.0% 33.6% 30.8% 30.3% 26.5% 29.7% 29.3%
3. Unmanipulated Haploidentical HSCT
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Huang XJ, et al. BMT, 2006, 38:291
Huang XJ, et al. Blood, 2006, 107(8):3065-3073
Huang XJ, et al. Clin Cancer Res, 2009, 15: 4777-4783
Huang XJ, et al. BBMT. 2011 Feb;17(2):197-204
Part I Conclusions
• G-BM combined with PBSC from haploidentical family donors, without in vitro TCD, may be used as a good source of stem cells for allo-HSCT
• There is no difference in OS and LFS between patients receiving allografts from PMRD and URD
3. Unmanipulated Haploidentical HSCT
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3.Unmanipulated Haploidentical HSCT
Huang XJ, et al Unpublished , Blood Reversed
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Part II : Strategy to Improve the Clinical Results
1• Modified Donor Lymphocyte Infusion(DLI)
2• Manipulating the Graft
3• Optimize KIR ligand match/mismatch
4• Improve Immune Reconstitution
3. Unmanipulated Haploidentical HSCT
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Relapse Remains a Problem after HSCT
High risk leukemiaHigh risk leukemia
Huang XJ et al, Biol Blood Marrow Transplant. 2009 Feb;15(2)
Especiallyfor advancedleukemia(58%- 74%)
3. Unmanipulated Haploidentical HSCT
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Strategy-1 Our modified DLI
G-CSF primed peripheral blood progenitor cells instead of steady
donor lymphocyte harvests
Short-term CsA/MTX for prevention of
DLI-associated GVHD
GPBSCIGPBSCI
Huang XJ et al, LEUKEMIA, 2006 ; 20 , 365-368Huang XJ et al, Bone Marrow Transplant. 2009;44(5):309-16
3. Unmanipulated Haploidentical HSCT
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GVHD prophylaxis Reduced GVHD occurrence
Huang XJ, et al. Hematologica, 2007,92:414-417
None
MTX
3. Unmanipulated Haploidentical HSCT
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Prevention of relapse using modified DLI can
significantly increase survival following HLA-
mismatched/Haplo-identical HSCT in patients
with advanced-stage, acute leukemia
3. Unmanipulated Haploidentical HSCT
Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted
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Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted
Diagnosis N=75 Jan,2003 - Sep,2010
AMLN=42
>CR2 7
NR+REL 35
ALLN=33
>CR2 8
NR+REL 25
Patients Characteristic
3. Unmanipulated Haploidentical HSCT
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Prophylactic GPBPCI
• Performed at 70 (20 ~ 314) d after HSCT
• MNC 1.0 (0.5-2.0) 108/kg • CD3+ 0.93 (0.2-2.12) 108/kg
• No patients had profound and lasting pancytopenia after the prophylactic infusion
3. Unmanipulated Haploidentical HSCT
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Cumulative incidence of grade to acute Ⅲ ⅣGVHD
GVHD prophylaxis < 2w: 49.5%
GVHD prophylaxis 2 ~4w: 31.6%
GVHD prophylaxis 4 ~6w: 14.4%
GVHD prophylaxis >6w: 9.3%
The risk factor of DLI-associated acute GVHD
Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted
3. Unmanipulated Haploidentical HSCT
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Cumulative incidence of aGVHD
Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted
P=0.55P=0.55
3. Unmanipulated Haploidentical HSCT
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Cumulative incidence of cGVHD
Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted
P=0.42P=0.42
3. Unmanipulated Haploidentical HSCT
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Cumulative incidence of TRM
Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted
P=0.95P=0.95
3. Unmanipulated Haploidentical HSCT
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Cumulative incidence of relapse
Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted
P=0.018P=0.018
3. Unmanipulated Haploidentical HSCT
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Probability of OS
Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted
(P=0.013)(P=0.013)
3. Unmanipulated Haploidentical HSCT
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Lower relapse rate, a similar NRM, and a higher
survival probability compared with non-DLI
Can significantly increase the survival of
patients with advanced-stage, acute leukemia
even after HLA-mismatched, T-cell-replete HSCT
Modified prophylactic DLI after HLA-mismatched/Haplo-identical HSCT
Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted
3. Unmanipulated Haploidentical HSCT
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Risk stratification-directed DLI could reduce relapse of standard-risk acute
leukemia after allo-HSCT
Institute of Hematology Peking UniversityBeijing, China
ASH 2111 Oral Presentation
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Efficacy of intervention
Groups 3yr-Relapse TRM OS LFSA 18.1% 19.7% 66.0% 61.6% B 68.0% 11.2% 23.9% 20.8% C 29.8% 15.6% 55.4% 52.5%
ASH 2111 Oral Presentation
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Strategy-1 Conclusion
m-DLI can be used for the
treatment and prophylaxis of relapse
after haplo-identical HSCT
3. Unmanipulated Haploidentical HSCT
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Dose of Th17 and GVHD
0 50 100 1500
20
40
60
80
Low Th17 groupHigh Th17 group
days after transplantation
Cu
mu
lati
ve in
cid
en
ce Dose of Th17 and GVHD
0 50 100 1500
20
40
60
80
Low Th17 groupHigh Th17 group
days after transplantation
Cu
mu
lati
ve in
cid
en
ce
Tc17 dose and GVHD
0 50 100 1500
20
40
60
80Low Tc17 groupHigh Tc17 group
days after transplantation
Cu
mu
lati
ve in
cid
en
ce Tc17 dose and GVHD
0 50 100 1500
20
40
60
80Low Tc17 groupHigh Tc17 group
days after transplantation
Cu
mu
lati
ve in
cid
en
ce
0 50 100 1500
20
40
60
80
100
Low dose
other dose
High dose
days after transplantation
Cum
ulat
ive
inci
denc
e0 50 100 150
0
20
40
60
80
100
Low dose
other dose
High dose
days after transplantation
Cum
ulat
ive
inci
denc
ep=0.005
p=0.00017
p=0.001
( n=12)
( n=17)
( n=12)
HuangXJ , et al,
Eur J Immunol. 2011 Feb;41(2):514-26
Predictive value of Th17 cells and Tc17 cells in allo-graft on acute GVHD
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Treating donor mice with rhIL-11 and rhG-CSF promotes transplant-tolerance and preserves the effects of GVL after allogeneic bone
marrow transplantation
HuangXJ, et al. Leuk Res. 2009 Jan;33(1):123-8
Effects of different cytokines treatment on the recipients’ T cells proliferation activity in response to host alloantigens +14 d after BMT.
Effects of different cytokines treatment on the recipients’ T cells proliferation activity in response to host alloantigens +14 d after BMT.
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Strategy-2 Conclusion
We may decrease the incidence of GVHD by manipulating the cell contents or function of graft? Mobilization with IL-11 plus G-CSF ?
3. Unmanipulated Haploidentical HSCT
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Strategy-3 KIR ligand match/mismatch to outcome on pretransplantation category
aGVHD TRM Relapse
OS
KIR mismatchKIR mismatch
KIR matchKIR match
Huang XJ, et al. Biol Bone Marrow Transplant, 2008,14(3)
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Strategy-3 Conclusion
• KIR ligand mismatch is associated with higher aGVHD, a greater relapse rate, and inferior survival in our haploidentical GIAC protocol---Donor Slection ?
3. Unmanipulated Haploidentical HSCT
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70.0060.0050.0040.0030.0020.0010.000.00
Months posttransplant
1.0
0.8
0.6
0.4
0.2
0.0Prop
ortio
ns o
f pat
ient
s (%
)
300/ul-小于censored
300/ul-大于等于censored
300/ul小于
300/ul大于等于
Cutoff ?按照 值 划分
70.0060.0050.0040.0030.0020.0010.000.00
Months posttransplant
1.0
0.8
0.6
0.4
0.2
0.0Prop
ortio
ns o
f pat
ient
s (%
)
300/ul-小于censored
300/ul-大于等于censored
300/ul小于
300/ul大于等于
Cutoff ?按照 值 划分
ALC-30 >300/ul
ALC-30 >300/ul
ALC-30≤300/ul
ALC-30≤300/ul
P<0.001P<0.001 n=206n=206
Strategy-4 Immune Reconstitution
Huang XJ, et al. Bone Marrow Transplant, 2009,43: 29-36
TRM
3. Unmanipulated Haploidentical HSCT
70.0060.0050.0040.0030.0020.0010.000.00
Months posttransplant
1.0
0.8
0.6
0.4
0.2
0.0
Leuk
emia
-fre
e su
rvival
300/ul-censored小于
300/ul-大于等于censored
300/ul小于
300/ul大于等于Cutoff ?按照 值 划分
70.0060.0050.0040.0030.0020.0010.000.00
Months posttransplant
1.0
0.8
0.6
0.4
0.2
0.0
Leuk
emia
-fre
e su
rvival
300/ul-censored小于
300/ul-大于等于censored
300/ul小于
300/ul大于等于Cutoff ?按照 值 划分
ALC-30>300/ulALC-30>300/ul
ALC-30≤300/ulALC-30≤300/ul
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0
200
400
600
800
1000
1200
1400
1600
1800
2000
30 60 90 120 180 270 360
CD3+
cel
ls/u
l
Days f rom transpl antati on
HLA matchHLA mi smatchNormal
**
The counts of reconstituted CD3+ cells (cells/μl ) were significantly lower in HLA-mismatched patients at days 30 than those in HLA-matched patients, which reached normal level at days 60 in both HLA-matched and -mismatched patients. ** P < 0.001
The counts of reconstituted CD3+ cells (cells/μl ) were significantly lower in HLA-mismatched patients at days 30 than those in HLA-matched patients, which reached normal level at days 60 in both HLA-matched and -mismatched patients. ** P < 0.001
HuangXJ, J Cli Imm Online Publication
Comparison of Reconstituted T cells subgroup between HLA match and mismatch
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0
100
200
300
400
500
600
700
800
30 60 90 120 180 270 360Days af ter transpl antati on
CD4+
cel
ls/u
lHLA matchHLA mi smatchNormal
** * ***
The counts of reconstituted CD4+ cells (cells/μl ) were significantly lower in HLA-mismatched patients at days 30, 60, 90, and 120 than those in HLA-matched patients, which did not reached normal level until 360 in both HLA-matched and mismatched patients, respectively. * P < 0.05, ** P < 0.001
The counts of reconstituted CD4+ cells (cells/μl ) were significantly lower in HLA-mismatched patients at days 30, 60, 90, and 120 than those in HLA-matched patients, which did not reached normal level until 360 in both HLA-matched and mismatched patients, respectively. * P < 0.05, ** P < 0.001
HuangXJ, J Cli Imm Online Publication
Comparison of Reconstituted T cells subgroup between HLA match and mismatch
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Strategy-4 Conclusion
Novel approach to improve the recovery of immune reconstitution are greatly required. IL-2 after HSCT ?
A Randomized Clinical Trial Is Undergoing For Evaluing IL-2 After Haplo-identical HSCT In PUIH
3. Unmanipulated Haploidentical HSCT
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Acknowledgements
Stem cell collection centerHai-Yin ZhengHong XuQing ZhaoSu Wang
Department of Bone Marrow Transplant Dai-Hong LiuFeng-Rong WangHuan ChenJing-Zhi WangKai-Yan LiuLan-Ping XuWei HanXiao-Hui ZhangYu-Hong ChenYu Wang
Laboratory of PUIHDan LiYa-Zhen QinYan-Rong LiuYue-Yun Lai