haploidentical hematopoietic stem cell transplantation for hematological malignancies xiao-jun huang...

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

1

EducationClinic

Research

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%

• 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

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

Effects of G-CSF on Bone Marrow in Healthy Donors

HuangXJ, et al. Clin Transplant 2011: 25: 13–23


Immunoregulatroy Effects after G-CSF Administration to Healthy Donors

Huang XJ, et al. Biol Blood Marrow Transplant.2011;17(2):197-204


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


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


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


Probability of aGVHD with locus disparity

Huang XJ, et al. Bone Marrow Transplant. 2006;38(4):291-7.


DFS & OS compared with HLA Matched Donor

Huang XJ, et al. Blood, 2006, 107(8):3065-3073


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


Relapse compared with Identical Sibling （ ISD）

HuangXJ, et al. Biol Blood Marrow Transplant. 2011;17(6)

Haplo=81

Identical=36


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


Superior Graft-versus-Leukemia effect

HaploidenticalHLA-identical

sibling

High risk acute leukemia

HuangXJ, et al. Biol Blood Marrow Transplant. 2011 ;17(6):821-30


No. of Haploidentical HSCT accumulated in PUIH

PUIH data


The changing of Composition of Haploidentical allo-HSCT in PUIH from 2007 to 2009

PUIH data


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)

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%


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

Huang XJ, et al Unpublished ， Blood Reversed

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


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%)


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


GVHD prophylaxis Reduced GVHD occurrence

Huang XJ, et al. Hematologica, 2007,92:414-417

None

MTX


Prevention of relapse using modified DLI can

significantly increase survival following HLA-

mismatched/Haplo-identical HSCT in patients

with advanced-stage, acute leukemia


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


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


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



Cumulative incidence of aGVHD


P=0.55P=0.55


Cumulative incidence of cGVHD


P=0.42P=0.42


Cumulative incidence of TRM


P=0.95P=0.95


Cumulative incidence of relapse


P=0.018P=0.018


Probability of OS


(P=0.013)(P=0.013)


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



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

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

Strategy-1 Conclusion

m-DLI can be used for the

treatment and prophylaxis of relapse

after haplo-identical HSCT


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


Cu

mu

lati

ve in

cid

en

ce

Tc17 dose and GVHD

0 50 100 1500

20

40

60

80Low Tc17 groupHigh Tc17 group


Cu

mu

lati

ve in

cid

en

ce Tc17 dose and GVHD

0 50 100 1500

20

40

60

80Low Tc17 groupHigh Tc17 group


Cu

mu

lati

ve in

cid

en

ce

0 50 100 1500

20

40

60

80

100

Low dose

other dose

High dose


Cum

ulat

ive

inci

denc

e0 50 100 150

0

20

40

60

80

100

Low dose

other dose

High dose


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

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.


We may decrease the incidence of GVHD by manipulating the cell contents or function of graft? Mobilization with IL-11 plus G-CSF ?


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)


• KIR ligand mismatch is associated with higher aGVHD, a greater relapse rate, and inferior survival in our haploidentical GIAC protocol---Donor Slection ?


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


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


70.0060.0050.0040.0030.0020.0010.000.00


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小于

300/ul大于等于Cutoff ?按照值划分

70.0060.0050.0040.0030.0020.0010.000.00


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

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

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


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


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

haploidentical hematopoietic stem cell transplantation for hematological malignancies xiao-jun huang...

Documents

cases of hsct

depleted hsct

hsct mnc

engraftment huang xj

acute gvhd huang xj

allohsct cases

bone marrow transplant

gbm huang xj