YU WANG, MDBeijing, China

• Assistant Professor, Stem Cell Transplant, Peking University Institute of Hematology

• Dr. Yu Wang obtained her medical degree from Peking University Medical College, China and underwent internal medicine training at Peking University People’s Hospital. Thereafter, she completed training in Hematology at Peking University Institute of Hematology. Dr. Wang has published in numerous peer reviewed journals. She is one of the main prize winners of Second Prize of National Science and Technology Award and Second Prize of Chinese Medical Science and Technology Award. She serves as the vice-president of young commissioner, Beijing Society of Hematology, Beijing Medical Association. Areas of Interest: Risk stratification, management of post- HSCT relapse, haploidentical HSCT

Donor selection for

haploidentical hematopoietic

stem cell transplantation

Yu Wang , Ying-Jun Chang, Xiao-Jun Huang*

Peking University Institute of Hematology

Peking University People’s Hospital

Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation

Questions need to be answered

• ideal donor selection: many aspects

• haploidentical HSCT : unlimited donor and

availabilities of more than one donor

• whether one donor preferred among various

haploidentical donors available

Wang Y, Huang XJ, et al. Cancer 2013;119:978-85

Introduction

S.O. Ciurea, R.E. Champlin

Biol Blood Marrow Transplant 2013

ex-vivo TCD

CD3/CD19 depletion

immune tolerance induced by G-CSF

PT/CY

(Blood. 2014; 124(6):843-850)

0

1000

2000

3000

4000

196419821984198619881990199219941996199820002002200520072009201120130

200

400

600

800

1000

1200

1400

1600

1800

2000

1990 1996 2002 2004 2006 2008 2010 2012

Number of HSCT cases in PUIH

Purpose & Design• Really overcome HLA barrier ?

• Which factor impact donor selection?

• Did NIMA rule still play a role?

Introduction

• Haploidentical HSCT without in-vitro TCD

• 2002.5-2013.2 follow-up: 2013-12-1

• Conditioning: Modified Bu/Cy + ATG

• Graft: G-BM+G-PB

• collateral relatives excluded

Conditioning Regimen

ATG 2.5mg/kg(r)

-10

-8

-3

-5

-1

01

Ara-C 4g/m2

-6

-9

Bu 1mg/kg,q6h

CY 1.8g/m2

-4

MeCCNU 250mg/m2

-2

-7

BMSC

PBSC02

Methods

Wang Y, Huang XJ, et al. Cancer 2013;119:978-85

Patient & donor characteristics

results

Early + intermediate

advanced

HLA disparity 3 vs. 4-5/6

Results

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

Biol Blood Marrow Transplant 16: 482-489 (2010)

HLA loci

Huo et al. Clin transpl 2012 Fuji et al. BMT 2014

Biol Blood Marrow Transplant (2010)

Donor gender and age Results

Donor gender

Donor age

Female 46%

Male 39%

>30y 48%

<30y 25%

Female 24%

male 16%

>30y 22%

<30y 12%

Male 70%

Female 61%

<30y 78%

>30y 62%

Donor sex

Results

Donor age

>30y n=590 48%

<30y n=159 25%<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

Cu

mu

lative

In

cid

en

ce

of g

rad

e2

-4 a

cu

te G

VH

D

female n=226 34%

p=0.84

male n=685 39%Donor ageDonor gender

GVHD (exclude mother)

P<0.001

Multivariate &conclusion 1 Results

。002

• HLA disparity does not influence outcomes

• donor age affect outcomes, even exclude mother donor

• donor gender affect outcomes, but not after excluding maternal donor

Results

P=0.007

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

de3-

4 ac

ute

GV

HD

mother versus father

3-42-4

Mother 52%

Father 40%

mother n=301 22%

father n=412 13%

Mother 21%

Father 13%

NRM

father 74%

Mother 64%

OS

Results

412 vs 301 0.69 (0.55-0.86) 0.001

adverse impact of mother donors on acute GVHD persisted regardless of whether the

recipient was a son (HR = 1.34; P = .03) or a daughter(HR = 1.59; P = .001).

In contrast, maternal donors were associated with higher NRM and worse survival when

the recipient was a son (HR=2.04; P=.001and HR=1.49; P=.01), but not a daughter

• father is suprior to mother, regardless of donor age or

HLA disparity

Multivariate &conclusion 2

children vs. sibling

Results

P>0.05

sibling versus offspring 2-4

3-4

sibling n=386 37%

offspring n=111 16%

P=0.008

sibling n=386 9.8%

offspring n=111 6.5%

0 500 1000 1500 2000 2500 3000

0.0

0.2

0.4

0.6

0.8

1.0

days after transplantation

Cu

mu

lative

In

cid

en

ce

of N

RM

NRM OS

Results

• offspring is suprior to sibling with respect to

GVHD, regardless of donor gender, or HLA

disparity

Multivariate &conclusion 3

Father & sibling

ResultsSibling & father as a whole

2-4 3-4

<30y n=138 29%

>30y n=664 44%

P=0.006 P=0.02

>30y n=664 12%

<30y n=138 4%

0 500 1000 1500 2000 2500 3000

0.0

0.2

0.4

0.6

0.8

1.0

days after transplantation

Cu

mu

lative

In

cid

en

ce

of N

RM

NRM

>30y n=664 20%

<30y n=138 14%

P=0.03

OS<30y n=138 77%

>30y n=664 65%

0 1000 2000 3000 4000

0.0

0.2

0.4

0.6

0.8

1.0

days after transplantation

Cu

mu

lativ

e In

cid

en

ce o

f NR

M

father sister>30yrs to male

Father 71%

sister>30y to male 61%

P=0.046

OS

P=0.028

NRM

sister>30y to male 23%

Father 14%

P=0.08

Results

• sibling & father as a whole, donor age the most important

• sibling is not suprior to father, regardless of sex pair or HLA

disparity, even worse in sister older than 30yrs

Multivariate &conclusion 4

Father & sibling

Results

Results

P=0.024

Acute GVHD

2-4

NIPA n=26 46%

NIMA n=27 19%

NIMA vs. NIPA

among sibling

P=0.007

Mother to offspring n=55 44%

NIMA & offspring to mother

n=34 20%

NIMA & offspring to mother

vs. Mother to offspring

P=0.07

Father vs. Mother

vs. NIMA vs. NIPA

ResultsMultivariate &conclusion 5

• NIMA MM is suprior to both NIPA MM donor and maternal donor

• NIPA MM donor has a trend to be inferior to paternal donor

Father & sibling

ResultsIBMTR NON-TCD

Father & sibling

Results

Non-TCD half matched

Father & sibling

Results

Father & sibling

Results

Mechanism

Unclear & complicated, possible:

• materno-fetal microchemerism result in either tolerance or immunity

depending on the immunologic maturity of the host and the

antigenic disparity

• partial tolerance to the paternal HLA antigens might be counteracted

by reactivity to paternal minor histocompatibility antigens (mHA)

• mother exposure to IPA may develop anti-HLA Ab towards paternal

HLA molecules

• allo-reactivity towards H-Y antigen in mother-to-son

• NK allo-reactivity

summary

Summary

• Not abiding by the rule of HLA disparity, significant different

outcomes were achieved among various haploidentical donors

• Instead of HLA disparity, donor age and the family relationship were

important risk factors under “Beijing model”

• The underlying immunological mechanisms need further

investigation and to be validated by other treatment modalities

summary

Based on GVHD and NRM

Acknowledgements