Haploidentical Hematopoietic Stem Cell Transplantation for Hematological Malignancies
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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. Clinic. Research. Education. 1.

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Haploidentical Hematopoietic Stem Cell Transplantation for Hematological Malignancies

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Haploidentical hematopoietic stem cell transplantation for hematological malignancies

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


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

Clinic

Research

Education

1


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

The Cumulative Hematopoietic Stem Cell Transplantation (HSCT) Cases of PUIH

  • PUIH

  • The Largest HSCT center in Asia

  • Now >400 cases of HSCT per year

  • Now >60% Allo-HSCT cases are Unmanipulated Haploidentical HSCT

24%


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

Haploidentical Hematopoietic Stem Cell Transplantation for Hematological Malignancies

1

  • In vitro T-cell-depleted HSCT

2

  • Non-Myeloablative Haploidentical HSCT

3

  • Unmanipulated Myeloablative Haploidentical HSCT

Current Clinical Results

Strategy to Improve the Clinical Results


Giac protocol

3. Unmanipulated 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):3065-3073

Huang XJ, et al. Annals of Medicine, 2008, 40,444-455

Huang XJ, et al. Clin Cancer Res. 2009;15:4777-4783

Huang XJ, et al. BBMT. 2011 Jun;17(6):821-30.


Effects of g csf on bone marrow in healthy donors

Effects of G-CSF on Bone Marrow in Healthy Donors

3. Unmanipulated Haploidentical HSCT

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


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

3. Unmanipulated Haploidentical HSCT

Immunoregulatroy Effects after G-CSF Administration to Healthy Donors

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


Engraftment

3. Unmanipulated Haploidentical HSCT

Engraftment

n=348

n=348

CD34+ cells≥2.19×106/kg

Early stage

Advanced stage

CD34+ cells<2.19×106/kg

P=0.008

P<0.0001

Huang XJ, et al. Biol Blood Marrow Transplant,2009, 15(5):632-8


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

3. Unmanipulated Haploidentical HSCT

Characteristics of the Allo-Grafts

Huang XJ, et al. Bone Marrow Transplant, 2006, 38:291


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

3. Unmanipulated Haploidentical HSCT

Cumulative incidence of aGVHD

after HLA-mismatched allo-HSCT

Haplo=81

Identical=36

P=0.11

Huang XJ, et al. Biol Blood Marrow Transplant 2009, 15(2)

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


Probability of agvhd with locus disparity

Probability of aGVHD with locus disparity

3. Unmanipulated Haploidentical HSCT

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


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

3. Unmanipulated Haploidentical HSCT

DFS & OS compared with HLA Matched Donor

OS

LFS

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


Relapse compared with unrelated donor urd

3. Unmanipulated Haploidentical HSCT

Relapse compared with Unrelated Donor(URD)

PMRD=219

URD=78

PMRD=160

URD=60

Huang XJ, et al. Clin Cancer Res, 2009, 15:4777-4783


Relapse compared with identical sibling isd

3. Unmanipulated Haploidentical HSCT

Relapse compared with Identical Sibling(ISD)

Haplo=81

Identical=36

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


Os dfs compared with isd

3. Unmanipulated Haploidentical HSCT

OS & DFS compared with ISD

Haplo=81

Identical=36

PMRD=81

ISD=36

P = 0.029

P = 0.048

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


Superior graft versus leukemia effect

3. Unmanipulated Haploidentical HSCT

>

Haploidentical

HLA-identical sibling

Superior Graft-versus-Leukemia effect

High risk

acute leukemia

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


No of h aploidentical hsct accumulated in puih

No. of Haploidentical HSCT accumulated in PUIH

3. Unmanipulated Haploidentical HSCT

PUIH data


The changing of composition of h aploidentical allo hsct in puih from 2007 to 200 9

3. Unmanipulated Haploidentical HSCT

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

PUIH data


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

Studies on HLA-mismatched/haploidentical stem cell transplantation (GIAC)


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

3. Unmanipulated Haploidentical HSCT

Composition of HSCT Donor Types

in 24 Transplant Units in China

PUIH collected


Part i conclusions

3. Unmanipulated Haploidentical HSCT

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

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


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

3.Unmanipulated Haploidentical HSCT

Huang XJ, et alUnpublished,Blood Reversed


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

3. Unmanipulated Haploidentical HSCT

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


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

High risk leukemia

3. Unmanipulated Haploidentical HSCT

Relapse Remains a Problem after HSCT

Especially

for advanced

leukemia

(58%- 74%)

Huang XJ et al, Biol Blood Marrow Transplant. 2009 Feb;15(2)


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

3. Unmanipulated Haploidentical HSCT

Strategy-1Our modified DLI

G-CSF primed peripheral blood

progenitor cells instead of steady

donor lymphocyte harvests

GPBSCI

Short-term CsA/MTX

for prevention of

DLI-associated GVHD

Huang XJ et al, LEUKEMIA, 2006;20,365-368

Huang XJ et al, Bone Marrow Transplant. 2009;44(5):309-16


Gvhd prophylaxis reduced gvhd occurrence

3. Unmanipulated Haploidentical HSCT

GVHD prophylaxis Reduced GVHD occurrence

None

MTX

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


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

Prevention of relapse using modified DLI can significantly increase survival following HLA-mismatched/Haplo-identical HSCT in patients with advanced-stage, acute leukemia

3. Unmanipulated Haploidentical HSCT

Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

3. Unmanipulated Haploidentical HSCT

Patients Characteristic

Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted


Prophylactic gpbpci

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

3. Unmanipulated Haploidentical HSCT


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

3. Unmanipulated Haploidentical HSCT

The risk factor of DLI-associated acute GVHD

Cumulative incidence of grade Ⅲ to Ⅳ acute GVHD

GVHD prophylaxis < 2w: 49.5%

GVHD prophylaxis 2~4w: 31.6%

GVHD prophylaxis 4~6w: 14.4%

GVHD prophylaxis >6w: 9.3%

Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted


Cumulative incidence of agvhd

Cumulative incidence of aGVHD

3. Unmanipulated Haploidentical HSCT

P=0.55

Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted


Cumulative incidence of cgvhd

Cumulative incidence of cGVHD

3. Unmanipulated Haploidentical HSCT

P=0.42

Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted


Cumulative incidence of trm

Cumulative incidence of TRM

3. Unmanipulated Haploidentical HSCT

P=0.95

Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted


Cumulative incidence of relapse

Cumulative incidence of relapse

3. Unmanipulated Haploidentical HSCT

P=0.018

Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted


Probability of os

Probability of OS

3. Unmanipulated Haploidentical HSCT

(P=0.013)

Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

3. Unmanipulated Haploidentical HSCT

Modified prophylactic DLI after

HLA-mismatched/Haplo-identical HSCT

  • 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

Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

Risk stratification-directed DLI could reduce relapse of standard-risk acute leukemia after allo-HSCT

Institute of Hematology Peking University

Beijing, China

ASH 2111 Oral Presentation


Efficacy of intervention

Efficacy of intervention

Groups 3yr-Relapse TRMOSLFS

A 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

3. Unmanipulated Haploidentical HSCT

Strategy-1 Conclusion

m-DLI can be used for the treatment andprophylaxis of relapse afterhaplo-identical HSCT


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

Predictive value of Th17 cells and Tc17 cells in allo-graft on acute GVHD

p=0.00017

(n=12)

p=0.005

(n=17)

(n=12)

p=0.001

HuangXJ,et al,

Eur J Immunol. 2011 Feb;41(2):514-26


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

Treating donor mice with rhIL-11 and rhG-CSF promotes transplant-tolerance and preserves the effects of GVL after allogeneic bone marrow transplantation

Effects of different cytokines treatment on the recipients’ T cells proliferation activity in response to host alloantigens +14 d after BMT.

HuangXJ, et al. Leuk Res. 2009 Jan;33(1):123-8


Strategy 2 conclusion

Strategy-2 Conclusion

3. Unmanipulated Haploidentical HSCT

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

Strategy-3 KIR ligand match/mismatch to outcome on pretransplantation category

TRM

Relapse

aGVHD

KIR mismatch

KIR match

OS

Huang XJ, et al.

Biol Bone Marrow Transplant, 2008,14(3)


Strategy 3 conclusion

3. Unmanipulated Haploidentical HSCT

Strategy-3 Conclusion

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


Strategy 4 immune reconstitution

P<0.001

n=206

ALC-30>300/ul

ALC-30≤300/ul

ALC-30≤300/ul

ALC-30>300/ul

3. Unmanipulated Haploidentical HSCT

Strategy-4 Immune Reconstitution

TRM

Huang XJ, et al. Bone Marrow Transplant, 2009,43: 29-36


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

Comparison of Reconstituted T cells subgroup between HLA match and mismatch

**

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


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

Comparison of Reconstituted T cells subgroup between HLA match and mismatch

**

*

*

**

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 OnlinePublication


Strategy 4 conclusion

3. Unmanipulated Haploidentical HSCT

Strategy-4 Conclusion

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


Haploidentical hematopoietic stem cell transplantation for hematological malignancies

Acknowledgements

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

Stem cell collection center

Hai-Yin Zheng

Hong Xu

Qing Zhao

Su Wang

Laboratory of PUIH

Dan Li

Ya-Zhen Qin

Yan-Rong Liu

Yue-Yun Lai


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