in-vitro t-cell depletion is not necessary for haplo ...€¦ · beijing protocol for haplo-hsct...
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In-vitro T-cell Depletion is Not Necessary
for Haplo-identical Transplantation
Xiao-Jun Huang M.D.
Peking University Institute of Hematology (PUIH),
Peking University People’s Hospital ,
Beijing Key Laboratory of HSCT,
Beijing, P.R.China
Professor . Xiaojun HUANG
In-vitro T-cell Depletion is Not Necessaryfor Haplo-identical Transplantation
Disclosure of Interest: Nothing to Disclose
Peking University Institute of Hematology,
Peking University People’s Hospital &
Beijing Key Laboratory of HSCT,
Beijing, P.R.China
Professor . Xiaojun HUANG
Outline
• 1 The Feasibility of T-cell Replete (TCR)
Haplo-HSCT
• 2 Comparsion of TCR with of In- vitro T-cell
Depletion (TCD) Haplo-HSCT
• 3 Summary
None- T
cell depletion
in vitro T
cell depletion
We can overcome HLA barrier by manipulating T cell function but not T-cell depletion
Immune-regulatory Effects after G-CSF Administration to Healthy Donors
Huang XJ, et al. Biol Blood Marrow Transplant.2011;17(2):197-204
1.1 Beijing Protocol
Beijing Protocol for Haplo-HSCT
• 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. Bone Marrow Transplant, 2006, 38:291 Lu DP, et al. Blood, 2006, 107(8):3065-3073 Huang XJ, et al. Clin Cancer Res. 2009;15:4777-4783 Huang XJ, et al. Blood. 2012;119(23):5584-5590. Huang XJ, et al. Cancer. 2013 Mar 1;119(5):978-85.
1.1 Beijing Protocol
Haplo-HSCT cases accumulated in PUIH, Beijing
Peking University Institute of Hematology(PUIH)Data
0
200
400
600
800
1000
1200
1400
5 34 99
189 300
435 535
729
921
1130
1359
1.1 Beijing Protocol
patients with leukemia
• 756 patients, with a median age of 25, were enrolled.
• Conditioning :
moidifed Bu/Cy
• Graft: unmanipulated G-BM+G+PB
• GVHD prophylaxis:
CSA + low dose MTX+MMF
Huang XJ, et al. Cancer. 2013 Mar 1;119(5):978-85.
1.1 Beijing Protocol
p=0.068
Engraftment (Disease Status)
ANC Platelet
p=0.113
Huang XJ, et al. Cancer. 2013 Mar 1;119(5):978-85.
1.1 Beijing Protocol
aGVHD 2-4 (HLA Disparity)
p=0.39 p=0.08
1.1 Beijing Protocol
Huang XJ, et al. Cancer. 2013 Mar 1;119(5):978-85.
aGVHD 3-4 (HLA Disparity)
p=0.75
1.1 Beijing Protocol
Huang XJ, et al. Cancer. 2013 Mar 1;119(5):978-85.
Disease Type Disease Status
p=0.001
cGVHD Extensive
p=0.527
1.1 Beijing Protocol
Huang XJ, et al. Cancer. 2013 Mar 1;119(5):978-85.
LFS (HLA disparity)
p=0.243
1.1 Beijing Protocol
Huang XJ, et al. Cancer. 2013 Mar 1;119(5):978-85.
Haplo-HSCT has similar therapeutic effect compared with HLA matched sibling donor or matched unrelated donor HSCT
1.1 Beijing Protocol
Haplo-HSCT patients can achieve desirable health-related quality of life comparable to MSD-HSCT patients
HRQoL measure
ISD(n=173) mean±s,d.
PMRD (n=177) mean±s,d.
P value
Physical
Physical component (PCS) 46.9±10.3 50.3±8.8 0.001
Physical functioning 82.7±18.3 87.2±15.4 0.012
Role functioning-physical 57.4±41.6 64.3±39.5 0.113
Bodily pain 75.5±23.0 84.6±18.7 < 0.001
General health 60.6±22.6 68.2±20.1 0.001
Psychological
Mental component (MCS) 52.2±9.9 53.9±8.9 0.096
Vitality 66.6±20.6 73.6±15.6 < 0.001
Social functioning 72.8±24.1 75.5±23.4 0.295
Role functioning-emotional 65.9±40.7 77.2±35.4 0.006
Mental health 76.1±17.3 77.2±16.3 0.515
Higher score indicated better functioning with a population mean of 50 and an s.d.of 10. HuangXJ, Bone Marrow Transplant 2012; 47:1201-1205.
2. Health status in survivors
Multiple late effects (≥ 2)
The time interval
between the first and
the second late effect:
ISD: 51 days versus
PMRD: 262 days
(P=0.076).
Biol Blood Marrow Transplant. 2013 Feb 5. doi:pii: S1083-8791(13)00062-1. 10.1016/j.bbmt.2013.01.026
34.2% ± 0.1%
17.9% ± 0.1%
P=0.001
MSD Matched
Sibling
MUD Matched Unrelated
HRD Haplo
Related
Prospective, Multicenter Study for Chemotherapy and Haplo-HSCT in CR1 for AML patients
1.1 Beijing Protocol
Haplo-HSCT is Superior to Chemotherapy as Post-Remission Treatment for Intermediate or High risk AML in CR1
DFS Relapse
Huang XJ, et al. Blood. 2012;119:5584-5590
1.1 Beijing Protocol
Unmanipulated Haploidentical blood and marrow transplantation for patients with SSA
Huang XJ, et al.Bone Marrow Transplant. 2012;47:1507-12.
• 19 patients, with a median age of 19, were enrolled. Male/Female: 7/11
• Conditioning :
Bu+Cy+ATG (n=19)
• Graft: unmanipulated G-BM+G+PB
• GVHD prophylaxis:
CSA + low dose MTX+MMF
1.1 Beijing Protocol
Acute GVHD
Huang XJ, et al.Bone Marrow Transplant. 2012;47:1507-12.
Chronic GVHD
1.1 Beijing Protocol
Overall survival for SAA with Haplo-HSCT
Huang XJ, et al.Bone Marrow Transplant. 2012;47:1507-12.
1.1 Beijing Protocol
Summary of Haplo-HSCT in China
0
200
400
600
800
1000
2008 2009 2010 2011
415 510
654
840
303 334 388
559
216 203 283 346
21 47 46 78
Related Match Related Haplo Unrelated Cord
Haplo% 31.7% 30.5% 28.3% 30.7%
Chinese HSCT Register Group Data from 40 units
1.1 Myeloablative TCR Haplo-HSCT
Non-Myeloablative Haplo-HSCT with Unmanipulated S-BM
• Reduced-Intensity Conditioning :
Fludarabine+ CTX+TBI
• Graft: PBMC without Manipulation of T cells
• GVHD prophylaxis:Hi-CTX+MMF+FK506
Johns Hopkins University U.S.A
Patients (n)
Disease Engraftment
2-4 aGHVD
cGVHD
TRM Relapse LFS Reference
210 AL/NHL/CML/MDS
87% 27% 13% 18% 55% 3y:32% Fuchs EJ.
et al. (2008)
50 AML/ALL/MDS
96% 32% 13% 31% 45% 1y:46% Fuchs EJ.
et al. (2011)
Fuchs EJ, et al. BBMT. 2008 Jun;14(6):641-50; Blood.2011 Jul 14;118(2):282-8
1.2 Non- Myeloablative TCR Haplo-HSCT
Summary of TCR Haplo-HSCT
Patients
Disease
Conditioning
Graft GVHD
Prophylaxis GR aGVHD cGVHD TRM LFS Nation
Reference
66 AL/M
DS
RIC:TBI/flu/Bu/ATG/me
lphalan PB or BM FK506 6.1% (II-IV)38% 57.5%
28.8@4years
Japan Kurokawa(2010)
83 AL/M
DS RIC:Bu/Flu/
ATG PB/No CsA+MTX 0 24% 28%
17%@1year
AML/MDS CR53%-
60%;AML RE9%
Korea Lee(2011
)
50 AL/M
DS RIC:Cy/Flu/
TBI BM/No
Cy(HD)+FK506+MMF
4% (II-IV)32% 13% 7%@1y
ear 46%@1yea
r U.S.A
Fuchs(20
11)
21 AL/CML
ST:Bu/Cy/MeCCNU/A
TG PB/No
CsA+MTX+MMF
0 (II-
IV)33.8% 39.5% 20%@2
years
55.6%@2years
China Yu(2012)
80
AML/ALL/CML/Others
ST:Thiotepa +Bu+Flu or
others BM/No
ATG+CSA+MTX+MMF+CD
25 9% (II-IV)24% 17% 34%
38% @3 yrs
Italy
BartolomeoD
(2013)
820 AL/CML/NHL/AA
ST:Bu/Cy/Ara-
C/MeCCNU+ATG
BM+PB/No
CsA+MTX+MMF
<1%
(II-IV)42.9% (III-IV)14.0%
Total 53.7% Extensive
23.4% @2years
21.4%@2 years
SR68.1% HR47.1%
China Huang(2
013)
M.D Anderson TCD Vs. TCR Design
3.3 TCD Vs. TCR-M.D Anderson
Champlin RE, et al. Biol Blood Marrow Transplant. 2012 Dec;18(12):1835-44.
TCD TCR
Conditioning ST:Melphalan+ Thiotepa+Flu
+ATG
ST:Melphalan+ Thiotepa+Flu (part RIC)
Graft CD34+Selection
G-PB Unmanipulated
BM
GVHD Prophylaxis No Cy+FK506+MMF
aGvHD & cGvHD
Champlin RE, et al. Biol Blood Marrow Transplant. 2012 Dec;18(12):1835-44.
3.3 TCD Vs. TCR-M.D Anderson
Non Relapse Mortality
Champlin RE, et al. Biol Blood Marrow Transplant. 2012 Dec;18(12):1835-44.
3.3 TCD Vs. TCR-M.D Anderson
2-year OS and DFS
Champlin RE, et al. Biol Blood Marrow Transplant. 2012 Dec;18(12):1835-44.
3.3 TCD Vs. TCR-M.D Anderson
Beijing China
Perugia Italy
Tuebingen Germany
Johns Hopkins U.S.A
Protocol TCR CD34+ TCD
CD3-CD19- TCD
RIC-TCR
CD3 (/ul) 883 at day 90 100-200 at day 300
191 at day 100 Not avalaible
CD4 (/ul) 277 at day 360 Not avalaible 181 at day 400 220 at day 180
CD8 (/ul) 672 at day 90 230 at day 60 66 at day 100 Not avalaible
918 at day 180 570 at day 300 157 at day 400 Not avalaible
CD19 (/ul) 125 at day 360 Not avalaible Not avalaible Not avalaible
CD56 (/ul) 250 at day 30 400 at day 30 248 at day 20 Not avalaible
Comparison of IR between TCR and TCD haploidentical protocol
Huang XJ, et al. Semin Oncol. 2012 Dec;39(6):653-63
3.1 TCD Vs. TCR--General Comparison
3.1 TCD Vs. TCR--General Comparison
aGvHD 2-4 cGvHD
Graft Failure NRM
Overview of outcomes between TCR and TCD Haplo-HSCT
Based on the listed data
Summary of T-Cell Repleted HSCT
• Absence of technical expertise and cost of TCD
• High T-cell content of allografts potentially enhances the GVL effect
• Accelerated immune reconstitution
Advantages
• Potentially severe GVHD induced by T cells
Disadvantages
• TCR Haplo-HSCT protocols based on in-vivo modulation of T cell functions by G-CSF combined with ATG, CsA etal are simple and practicable.
• TCR Haplo-HSCT may have advantages: Engraftment, Lower NRM, rapid immune reconstitution, GVL effect and LFS/OS.
• cGvHD remains to be improved
Conclusion: In-vitro T-cell Depletion is Not Necessary
for Haplo-identical Transplantation
Acknowledgements
Stem cell collection center Hai-Yin Zheng Hong Xu Qing Zhao Su Wang
Department of Bone Marrow Transplant Dai-Hong Liu Feng-Rong Wang Huan Chen Jing-Zhi Wang Kai-Yan Liu Lan-Ping Xu Wei Han Xiao-Hui Zhang Yu-Hong Chen Yu Wang
Laboratory of PUIH Dan Li Ya-Zhen Qin Yan-Rong Liu Yue-Yun Lai
35th World Congress of the International Society of
Hematology, 2014
Organized by:
International Society of Hematology
Chinese Society of Hematology
President: Prof. Xiaojun Huang Co-chairs: Prof. Changgeng Ruan Prof. Saijuan Chen General Secretary: Prof. Kaiyan Liu Venue: China National Convention Center, Beijing, China Date: Sept. 4-7, 2014 Congress Website: www.ish2014.org