Kaiyan LIUPeking University People’s Hospital,

Peking University Institute of Hematology2015-8

Donor selection in haplo HSCT

北京大学血液病研究所INSTITUTE OF HEMATOLOGY

Current status of HSCT in China

Donor selection in haploHSCT

Donor specific anti-HLA antibodies (DSA) in haploHSCT

Outline

Overall HSCT activities in 2007-2014.6

02000400060008000

10000120001400016000

15970

2007 2008 2009 2010 2011 2012 2013 2014.6

Current HSCT in China

Trend in allogeneic HSCT from 2007-2014.6

2007 2008 2009 2010 2011 2012 2013

HLA identical sibling

Haploidentical relative

Unrelated PBSC

Unrelated CB

1 2 3 4 5 6 70

200

400

600

800

1000

1200

1400

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%

China Registry 2013

Unrelated18%

Auto 54%

Cord Blood 4%

RelatedMatched

24%

Re-lated

Match30%

Related Haplo32%

Unre-lated14%

Cord3%

auto22%

CIBMTR2007-2010

More Haplo and Allo-HSCT in China

Distribution of Transplantation Type

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%

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.

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

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

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

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 sexDonor age

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

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

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

0.0

0.2

0.4

0.6

0.8

1.0

days after transplantation

Cum

ulat

ive

Inci

denc

e of

gra

de2-

4 ac

ute

GV

HD

female n=226 34%

p=0.84

male n=685 39%

Donor ageDonor sex

Acute GVHD (Donor sex and age-exclude mother)

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

NIMA vs. NIPA(n=53)  Outcome and significant factors Hazard risk (95% CI) PⅡ-ⅣaGVHDNIMA/NIPA 3.109 (1.092-8.849) 0.034

NIMA vs. Mother to offspring (n=129)Outcome and significant factors Hazard risk (95% CI) PⅡ-ⅣaGVHDNIMA/mother to offspring 2.700 (1.261-5.780) 0.011Father to offspring vs. Mother to offspring vs. NIMA vs. NIPA (n=322) 　Outcome and significant factors Hazard risk (95% CI) PⅡ-ⅣaGVHD Mother donor 1NIMA 0.348(0.137-0.884) 0.026NIPA 1.115(0.584-2.129) 0.742Father donor 0.698(0.467-1.044) 0.080NIMA 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

Selection order Donor sourceMost preferred Child,NIMA-mismatched

2nd choice Younger brother,NIMA-mismatched

3ed choice Older sister,NIMA-mismatched or Father

4th choice OlderThe last choice Mother

Proposed Proposed algorithm for donor selection in haploidentical HSCT

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

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,2008,14:641-6502 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,

PGF5.9% Patient without

PGF

Patient with PGF

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

Limitations of these studies: 1) most studies were retrospective; 2) Primary graft failure including graft rejection (GR) and PGF3) 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

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

HLA 位点 MFI HLA 位点

Donor Recipient

07 15 04 15

HLA-DR

Donor specific antibody

Luminex200 flow analyzer

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,2009,14:4777Chang YJ,Huang XJ. Curr Opin Hematol,2012,19:454-461

• 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

• 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

MFI≤2000Group A 2000 ＜ MFI ＜

1000Group B

MFI≥10000Group 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

Group A Group B Group C

Results

Figure 2. Effects of DSA on TRM and OS

Relapse Infections Hemorrhage GVHD Others0

5

10

15

20

25

30

35

40

Patients with primary GF (n=22) Patients without primary GF (n=323)(%)

Results

Causes of death for patients underwent unmanipulated HBMT

HR 95% CI P valuePrimary 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 0.000DFS 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 0.000Relaspe Disease status 9.906 4.099-23.940 0.000TRM GR 1 PGF 0.209 0.056-0.790 0.021 No primary graft failure 0.031 0.0009-0.107 0.000ANC CD34 1.370 1.106-1.697 0.004PLT 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

• 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

Acknowledgements

Stem cell collection centerHai-Yin ZhengHong XuQing ZhaoSu Wang

Department of bone marrow transplant Xiao-Jun HuangKai-Yan Liu Dai-Hong Liu Lan-Ping XuHuan Chen Wei HanXiao-Hui ZhangYu-Hong Chen Feng-Rong Wang Jing-Zhi Wang Yu WangChen-Hua Yan Yuan-Yuan ZhangYu Ji Yu-Qian Sun

Laboratory of PUIHDan LiYa-Zhen QinYan-Rong LiuYue-Yun Lai