donor selection in Haplo Transplant. Kaiyan Liu

1. Kaiyan LIU
Peking University People’s Hospital,
Peking University Institute of Hematology
2015-8
Donor selection in haplo
HSCT
北京大学血液病研究所
INSTITUTE OF HEMATOLOGY

2. Current status of HSCT in China
Donor selection in haploHSCT
Donor specific anti-HLA antibodies
(DSA) in haploHSCT
Outline

3. Overall HSCT activities
in 2007-2014.6
0
2000
4000
6000
8000
10000
12000
14000
16000
15970
2007 2008 2009 2010 2011 2012 2013 2014.6
Current HSCT in China

4. Trend in allogeneic HSCT from
2007-2014.6
2007 2008 2009 2010 2011 2012 2013
HLA identical sibling
Haploidentical
relative
Unrelated PBSC
Unrelated CB
0
200
400
600
800
1000
1200
1400
1 2 3 4 5 6 7

5. Overall HSCT types
in 2007 to 2014.6
Haploidentical,7851,
28%
HLA identical
sibling,9477, 33%
Auto,5888, 21%
Unrelated
PBSC,4192, 15%
Unrelated CB and
syngeneic,3%

6. China Registry 2013
Unrelated
18%
Auto
54%
Cord
Blood 4%
Related
Matched
24%
Related
Match
29%
Related
Haplo
32%
Unrelat
ed
14%
Cord
3%
auto
22%
CIBMTR2007-2010
More Haplo and Allo-HSCT in China
Distribution of Transplantation Type

7. Total number and relative proportions of indications
for HSCT from 2007-2014.6
AML, 4763, 32%
ALL, 3420, 23%
CML, 1510, 10%
MM, 898, 6%
MDS, 1081, 7%
AA, 1086, 7%
NHL, 849, 6%
HD, 81, 1%
thalassemia , 209, 1% others,
1026,
7%

8. Chinease haploidentical SCT
• The establishment of GIAC：
G granulocyte colony-stimulating factor mobilization
I aggressive prophylaxis immunosuppression
A antithymocyte globulin
C combination of bone marrow and peripheral blood
Blood. 2006;107:3065-3073.

9. Wang Y, Liu DH, Liu KY, et al.Cancer. 2013;119:978-985.
Long-term follow-up of haploidentical HSCT
without in vitro T cell depletion for the
treatment of leukemia: nine years of experience
at a single center.
High risk
Standard risk
CML
AML
ALL

10. Lu DP, et al. Blood,2006,107(8):3065-3073
Haplo-HSCT vs. MSD
Unmanipulated HBMT can achieve
comparable outcomes with matched
related donor transplant

11. T-cell-replete haploidentical HSCT compared with
matched sibling HSCT and unrelated HSCT.
Luo Y, Xiao H, Lai X,et al.Blood. 2014 Sep 11. pii: blood-2014-04-571570.
os
DFS

13. Acute GVHD (Donor sex and age)
P=0.007
male n=686 39%
female n=524 46% >30y n=965 48%
<30y n=245 25%
P<0.001
Donor sex
Donor age

14. female n=686 24%
male n=524 16%
p=0.005 p=0.04
>30y n=965 22%
<30y n=245 12%
NRM (Donor sex and age)
Donor ageDonor sex

15. Donor sex Donor age
female n=356 24%
male n=393 16%
p=0.01 p=0.04
>30y n=590 22%
<30y n=159 12%
female n=524 61%
male n=686 70%
>30y n=965 62%
<30y n=245 78%
OS (Donor sex and age)
Donor sex Donor age

16. Donor sex Donor age
male n=393 39%
>30y n=590 48%
<30y n=159 25%
P<0.001
<30y n=239 25%
>30y n=672 44%
0 20 40 60 80 100
0.00.20.40.60.81.0
days after transplantation
CumulativeIncidenceofgrade2-4acuteGVHD
female n=226 34%
p=0.84
male n=685 39%
Donor ageDonor sex
Acute GVHD (Donor sex and age-exclude mother)

17. HLA disparity 3 vs. 4-5/6
GVHD
P<0.001
GVHD2-4 p=0.23
GVHD3-4 p=0.91
OS p=0.74
LFS p=0.55
n=678,407,125

18. NIMA vs. NIPA(n=53)
Outcome and significant factors Hazard risk (95% CI) P
Ⅱ-ⅣaGVHD
NIMA/NIPA 3.109 (1.092-8.849) 0.034
NIMA vs. Mother to offspring (n=129)
Outcome and significant factors Hazard risk (95% CI) P
Ⅱ-ⅣaGVHD
NIMA/mother to offspring 2.700 (1.261-5.780) 0.011
Father to offspring vs. Mother to offspring vs. NIMA vs. NIPA (n=322)
Outcome and significant factors Hazard risk (95% CI) P
Ⅱ-ⅣaGVHD
Mother donor 1
NIMA 0.348(0.137-0.884) 0.026
NIPA 1.115(0.584-2.129) 0.742
Father donor 0.698(0.467-1.044) 0.080
NIMA 不合供者优于 NIPA不合供者和 母亲供者；NIPA不合供者有不如父亲供者的趋势
Multivariate analysis

19. Selection order Donor source
Most preferred Child,NIMA-mismatched
2nd choice Younger brother,NIMA-
mismatched
3ed choice Older sister,NIMA-
mismatched or Father
4th choice Older
The last choice Mother
Proposed Proposed algorithm for donor selection
in haploidentical HSCT

20. Donor-specific anti-HLA antibodies were
associated with primary graft failure after
unmanipulated haploidentical blood and
marrow transplantation
Chang et al. Journal of Hematology &
Oncology (2015) 8:84

21. Complications, such as graft failure, remain
serious problems after Haplo-SCT
1 Aversa F, et al. J Clin Oncol,2005,23:3447-3454 3 Luznik L, et al. BBMT,2008,14:641-650
2 Federmann B, et al. Haematologica,97:1523-1531 4 Wang Y, et al. Cancer,2013,113:978-985
Authors, Year Patient
No.
Allografts Conditioning
regimen
Graft failure
Aversa et al. 2005 1 104 CD34 seleted PBSC MA 9%
Federmann et al. 2012 2 61 CD3/CD19-depleted PBSC RIC 8%
Luznik et al.2008 3 68 Unmanipulated bone marrow RIC 13%
Wang et al. 2013 4 756
Unmanipulated marrow and
blood grafts
MA 1%
Primary Poor
graft function,
PGF
5.9% Patient without
PGF
Patient with
PGF

22. Donor specific antibody
Donor specific antibody (DSA): anti-HLA antibodies, when
the specificity corresponded to a mismatched antigen of
donor
★ The prevalence of HLA antibodies caused by alloimmunization
★ Prevalance of HLA antibodies:
• Male: transfused 1.7%; non-transfused 1.0%
• Female: 24.4%
1.7% (0)
11.2% (1)
22.5% (2)
27.5% (3)
32.2% (4 or more pregnancies)
Yoshihara S,et al. Bone Marrow
Transplant,2012;47:1499-506

23. Limitations of these studies:
1) most studies were retrospective;
2) Primary graft failure including graft rejection (GR) and PGF
3) there were no training and validation groups.
MFI: median fluorescent intensity
Association of donor specific antibody with
graft failure after haplo-SCT
Yoshihara S,et al. Bone Marrow
Transplant,2012;47:1499-506

24. Definition of primary graft failure
Thomas' HCT, 4th Edition. Edited by Appelbaum F. R. et al.
1. Primary GF included graft rejection (GR) and poor
graft function (PGF).
2. GR is the failure to engraft neutrophils (ANC ≤0.5 ×
109/L) by day +28 for 3 consecutive days and the absence
of donor hematopoiesis.
3. Because delayed red cell engraftment may happen for
many months post-transplant and is more difficult to
evaluate in an unarguable manner, PGF was defined as the
presence of 3 cytopenic counts (ANC ≤0.5 × 109/L, platelet
≤20 × 109/L, or Hb≤80 g/L) beyond day +28 with a
transfusion requirement associated with hypoplastic-aplastic
bone marrow (BM), in the presence of complete donor
chimerism. Patients with evidence of severe GVHD or
hematologic relapse were excluded

25. HLA位点 MFI HLA位点
Donor Recipient
07 15 04 15
HLA-DR
Donor specific antibody
Luminex200 flow analyzer

26. Patients and methods
 A total of 345 subjects
 Unmanipulated haploidentical blood and marrow transplant protocol
 DSA were analyzed with a Luminex200 flow analyzer
Lu DP, et al. Bloood,2006,107:3065 Huang XJ, et al.Clin Cancer Res,2009,14:4777
Chang YJ,Huang XJ. Curr Opin Hematol,2012,19:454-461

27. • A total of 342 patients (99.1%) achieved sustained myeloid
engraftment.
Neutrophil engraftment: 13 days (range: 8-28 days)
Platelet engraftment:18 days (range, 6-330 days)
• Grade 2 through 4 acute GVHD: 42.7%±3.1%.
• After a median follow-up of 384 days (range, 25-784 days)
Chronic GVHD was 43.3%±3.1%.
The 2 year probablity of relapse: 8.8%±1.8%
TRM: 18.4±2.8%
DFS: 75.1%±2.9%
OS: 76.2%±3.0%
Results

28. • Of the 345 cases tested 87 (25.2%) were anti-HLA
antibody positive, including 44 male and 43 female.
• Of the positive cases, 39 (11.3%) were DSA positive.
Female: 16%
Male: 8%
• The median fluorescent intensity (MFI )of was 4726
(range, 504-19948).
Results

29. MFI≤2000
Group A
2000＜MFI＜1000
Group B
MFI≥10000
Group C
P value
Patient No. 316 (100%) 19 (100%) 10 (100%) NS
GR 0 (0%) 1 (6.3%) 2 (20%) 0.000
PGF 10 (3.2%) 5 (26.3%) 4 (40%) 0.000
GR+PGF 10 (3.2%) 6 (32.6%) 6 (60%) 0.000
Results
Group A
Group B
Group C
Figure 1. Effects of DSA on neutrophil and platelet engraftment

30. Group A Group B Group C
Results
Figure 2. Effects of DSA on TRM and OS

31. 0
5
10
15
20
25
30
35
40
Relapse Infections Hemorrhage GVHD Others
Patients with primary GF (n=22) Patients without primary GF (n=323)(%)
Results
Causes of death for patients underwent unmanipulated
HBMT

32. HR 95% CI P value
Primary graft failure
DSA MFI≥10000 1
2000≤MFI﹤10000 0.940 0.284-3.177 0.919
MFI﹤2000 0.187 0.048-0.730 0.016
OS
Disease status 2.839 1.702-4.736 0.000
GR 1
PGF 0.271 0.074-1.000 0.050
No primary graft failure 0.068 0.020-0.229 0.000
DFS
Disease status 3.593 2.212-5.836 0.000
GR 1
PGF 0.284 0.077-1.044 0.058
No primary graft failure 0.084 0.025-0.279 0.000
Relaspe
Disease status 9.906 4.099-23.940 0.000
TRM
GR 1
PGF 0.209 0.056-0.790 0.021
No primary graft failure 0.031 0.0009-0.107 0.000
ANC
CD34 1.370 1.106-1.697 0.004
PLT
CD34 1.483 1.187-1.852 0.001
DSA MFI≥10000 1
2000≤MFI﹤10000 3.074 1.137-8.311 0.027
MFI﹤2000 3.301 1.358-8.022 0.008
Multivariate analysis of factors associated with transplant outcomes

33. • We demonstrated that DSA might contribute to the
primary GF, including GR and PGF, after unmanipulated
haploidentical blood and marrow transplant.
• The onset of primary GF leads to inferior survival.
• Our results add new evidence that suggest DSA must
be considered when choosing among several
haploidentical donor sources.
Conclusion

34. Acknowledgements
Stem cell collection center
Hai-Yin Zheng
Hong Xu
Qing Zhao
Su Wang
Department of bone marrow transplant
Xiao-Jun Huang
Kai-Yan Liu
Dai-Hong Liu Lan-Ping Xu
Huan Chen Wei Han
Xiao-Hui Zhang
Yu-Hong Chen Feng-Rong Wang
Jing-Zhi Wang Yu Wang
Chen-Hua Yan Yuan-Yuan Zhang
Yu Ji Yu-Qian Sun
Laboratory of PUIH
Dan Li
Ya-Zhen Qin
Yan-Rong Liu
Yue-Yun Lai