in-vitro t-cell depletion is not necessary for haplo ...€¦ · beijing protocol for haplo-hsct...

In-vitro T-cell Depletion is Not Necessary

for Haplo-identical Transplantation

Xiao-Jun Huang M.D.

Peking University Institute of Hematology (PUIH),

Peking University People’s Hospital ,

Beijing Key Laboratory of HSCT,

Beijing, P.R.China

Professor . Xiaojun HUANG

In-vitro T-cell Depletion is Not Necessaryfor Haplo-identical Transplantation

Disclosure of Interest: Nothing to Disclose

Peking University Institute of Hematology,

Peking University People’s Hospital &

Beijing Key Laboratory of HSCT,

Beijing, P.R.China

Professor . Xiaojun HUANG

Outline

• 1 The Feasibility of T-cell Replete (TCR)

Haplo-HSCT

• 2 Comparsion of TCR with of In- vitro T-cell

Depletion (TCD) Haplo-HSCT

• 3 Summary

None- T

cell depletion

in vitro T

cell depletion

We can overcome HLA barrier by manipulating T cell function but not T-cell depletion

Immune-regulatory Effects after G-CSF Administration to Healthy Donors

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

1.1 Beijing Protocol

Beijing Protocol for Haplo-HSCT

• 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. Bone Marrow Transplant, 2006, 38:291 Lu DP, et al. Blood, 2006, 107(8):3065-3073 Huang XJ, et al. Clin Cancer Res. 2009;15:4777-4783 Huang XJ, et al. Blood. 2012;119(23):5584-5590. Huang XJ, et al. Cancer. 2013 Mar 1;119(5):978-85.

1.1 Beijing Protocol

Haplo-HSCT cases accumulated in PUIH, Beijing

Peking University Institute of Hematology（PUIH）Data

0

200

400

600

800

1000

1200

1400

5 34 99

189 300

435 535

729

921

1130

1359

1.1 Beijing Protocol

patients with leukemia

• 756 patients, with a median age of 25, were enrolled.

• Conditioning :

moidifed Bu/Cy

• Graft: unmanipulated G-BM+G+PB

• GVHD prophylaxis：

CSA + low dose MTX+MMF

Huang XJ, et al. Cancer. 2013 Mar 1;119(5):978-85.

1.1 Beijing Protocol

p=0.068

Engraftment (Disease Status)

ANC Platelet

p=0.113

Huang XJ, et al. Cancer. 2013 Mar 1;119(5):978-85.

1.1 Beijing Protocol

aGVHD 2-4 (HLA Disparity)

p=0.39 p=0.08

1.1 Beijing Protocol

Huang XJ, et al. Cancer. 2013 Mar 1;119(5):978-85.

aGVHD 3-4 (HLA Disparity)

p=0.75

1.1 Beijing Protocol

Huang XJ, et al. Cancer. 2013 Mar 1;119(5):978-85.

Disease Type Disease Status

p=0.001

cGVHD Extensive

p=0.527

1.1 Beijing Protocol

Huang XJ, et al. Cancer. 2013 Mar 1;119(5):978-85.

LFS (HLA disparity)

p=0.243

1.1 Beijing Protocol

Huang XJ, et al. Cancer. 2013 Mar 1;119(5):978-85.

Haplo-HSCT has similar therapeutic effect compared with HLA matched sibling donor or matched unrelated donor HSCT

1.1 Beijing Protocol

Haplo-HSCT patients can achieve desirable health-related quality of life comparable to MSD-HSCT patients

HRQoL measure

ISD(n=173) mean±s,d.

PMRD (n=177) mean±s,d.

P value

Physical

Physical component (PCS) 46.9±10.3 50.3±8.8 0.001

Physical functioning 82.7±18.3 87.2±15.4 0.012

Role functioning-physical 57.4±41.6 64.3±39.5 0.113

Bodily pain 75.5±23.0 84.6±18.7 < 0.001

General health 60.6±22.6 68.2±20.1 0.001

Psychological

Mental component (MCS) 52.2±9.9 53.9±8.9 0.096

Vitality 66.6±20.6 73.6±15.6 < 0.001

Social functioning 72.8±24.1 75.5±23.4 0.295

Role functioning-emotional 65.9±40.7 77.2±35.4 0.006

Mental health 76.1±17.3 77.2±16.3 0.515

Higher score indicated better functioning with a population mean of 50 and an s.d.of 10. HuangXJ, Bone Marrow Transplant 2012; 47:1201-1205.

2. Health status in survivors

Multiple late effects (≥ 2)

The time interval

between the first and

the second late effect:

ISD: 51 days versus

PMRD: 262 days

(P=0.076).

Biol Blood Marrow Transplant. 2013 Feb 5. doi:pii: S1083-8791(13)00062-1. 10.1016/j.bbmt.2013.01.026

34.2% ± 0.1%

17.9% ± 0.1%

P=0.001

MSD Matched

Sibling

MUD Matched Unrelated

HRD Haplo

Related

Prospective, Multicenter Study for Chemotherapy and Haplo-HSCT in CR1 for AML patients

1.1 Beijing Protocol

Haplo-HSCT is Superior to Chemotherapy as Post-Remission Treatment for Intermediate or High risk AML in CR1

DFS Relapse

Huang XJ, et al. Blood. 2012;119:5584-5590

1.1 Beijing Protocol

Unmanipulated Haploidentical blood and marrow transplantation for patients with SSA

Huang XJ, et al.Bone Marrow Transplant. 2012;47:1507-12.

• 19 patients, with a median age of 19, were enrolled. Male/Female: 7/11

• Conditioning :

Bu+Cy+ATG (n=19)

• Graft: unmanipulated G-BM+G+PB

• GVHD prophylaxis：

CSA + low dose MTX+MMF

1.1 Beijing Protocol

Acute GVHD

Huang XJ, et al.Bone Marrow Transplant. 2012;47:1507-12.

Chronic GVHD

1.1 Beijing Protocol

Overall survival for SAA with Haplo-HSCT

Huang XJ, et al.Bone Marrow Transplant. 2012;47:1507-12.

1.1 Beijing Protocol

Summary of Haplo-HSCT in China

0

200

400

600

800

1000

2008 2009 2010 2011

415 510

654

840

303 334 388

559

216 203 283 346

21 47 46 78

Related Match Related Haplo Unrelated Cord

Haplo% 31.7% 30.5% 28.3% 30.7%

Chinese HSCT Register Group Data from 40 units

1.1 Myeloablative TCR Haplo-HSCT

Non-Myeloablative Haplo-HSCT with Unmanipulated S-BM

• Reduced-Intensity Conditioning :

Fludarabine+ CTX+TBI

• Graft: PBMC without Manipulation of T cells

• GVHD prophylaxis：Hi-CTX+MMF+FK506

Johns Hopkins University U.S.A

Patients (n)

Disease Engraftment

2-4 aGHVD

cGVHD

TRM Relapse LFS Reference

210 AL/NHL/CML/MDS

87% 27% 13% 18% 55% 3y:32% Fuchs EJ.

et al. (2008)

50 AML/ALL/MDS

96% 32% 13% 31% 45% 1y:46% Fuchs EJ.

et al. (2011)

Fuchs EJ, et al. BBMT. 2008 Jun;14(6):641-50; Blood.2011 Jul 14;118(2):282-8

1.2 Non- Myeloablative TCR Haplo-HSCT

Summary of TCR Haplo-HSCT

Patients

Disease

Conditioning

Graft GVHD

Prophylaxis GR aGVHD cGVHD TRM LFS Nation

Reference

66 AL/M

DS

RIC:TBI/flu/Bu/ATG/me

lphalan PB or BM FK506 6.1% (II-IV)38% 57.5%

28.8@4years

Japan Kurokawa(2010)

83 AL/M

DS RIC:Bu/Flu/

ATG PB/No CsA+MTX 0 24% 28%

17%@1year

AML/MDS CR53%-

60%;AML RE9%

Korea Lee(2011

)

50 AL/M

DS RIC:Cy/Flu/

TBI BM/No

Cy(HD)+FK506+MMF

4% (II-IV)32% 13% 7%@1y

ear 46%@1yea

r U.S.A

Fuchs(20

11)

21 AL/CML

ST:Bu/Cy/MeCCNU/A

TG PB/No

CsA+MTX+MMF

0 (II-

IV)33.8% 39.5% 20%@2

years

55.6%@2years

China Yu(2012)

80

AML/ALL/CML/Others

ST:Thiotepa +Bu+Flu or

others BM/No

ATG+CSA+MTX+MMF+CD

25 9% (II-IV)24% 17% 34%

38% @3 yrs

Italy

BartolomeoD

(2013)

820 AL/CML/NHL/AA

ST:Bu/Cy/Ara-

C/MeCCNU+ATG

BM+PB/No

CsA+MTX+MMF

<1%

（II-IV）42.9% （III-IV）14.0%

Total 53.7% Extensive

23.4% @2years

21.4%@2 years

SR68.1% HR47.1%

China Huang(2

013)

M.D Anderson TCD Vs. TCR Design

3.3 TCD Vs. TCR-M.D Anderson

Champlin RE, et al. Biol Blood Marrow Transplant. 2012 Dec;18(12):1835-44.

TCD TCR

Conditioning ST:Melphalan+ Thiotepa+Flu

+ATG

ST:Melphalan+ Thiotepa+Flu （part RIC）

Graft CD34+Selection

G-PB Unmanipulated

BM

GVHD Prophylaxis No Cy+FK506+MMF

aGvHD & cGvHD

Champlin RE, et al. Biol Blood Marrow Transplant. 2012 Dec;18(12):1835-44.

3.3 TCD Vs. TCR-M.D Anderson

Non Relapse Mortality

Champlin RE, et al. Biol Blood Marrow Transplant. 2012 Dec;18(12):1835-44.

3.3 TCD Vs. TCR-M.D Anderson

2-year OS and DFS

Champlin RE, et al. Biol Blood Marrow Transplant. 2012 Dec;18(12):1835-44.

3.3 TCD Vs. TCR-M.D Anderson

Beijing China

Perugia Italy

Tuebingen Germany

Johns Hopkins U.S.A

Protocol TCR CD34+ TCD

CD3-CD19- TCD

RIC-TCR

CD3 (/ul) 883 at day 90 100-200 at day 300

191 at day 100 Not avalaible

CD4 (/ul) 277 at day 360 Not avalaible 181 at day 400 220 at day 180

CD8 (/ul) 672 at day 90 230 at day 60 66 at day 100 Not avalaible

918 at day 180 570 at day 300 157 at day 400 Not avalaible

CD19 (/ul) 125 at day 360 Not avalaible Not avalaible Not avalaible

CD56 (/ul) 250 at day 30 400 at day 30 248 at day 20 Not avalaible

Comparison of IR between TCR and TCD haploidentical protocol

Huang XJ, et al. Semin Oncol. 2012 Dec;39(6):653-63

3.1 TCD Vs. TCR--General Comparison

3.1 TCD Vs. TCR--General Comparison

aGvHD 2-4 cGvHD

Graft Failure NRM

Overview of outcomes between TCR and TCD Haplo-HSCT

Based on the listed data

Summary of T-Cell Repleted HSCT

• Absence of technical expertise and cost of TCD

• High T-cell content of allografts potentially enhances the GVL effect

• Accelerated immune reconstitution

Advantages

• Potentially severe GVHD induced by T cells

Disadvantages

• TCR Haplo-HSCT protocols based on in-vivo modulation of T cell functions by G-CSF combined with ATG, CsA etal are simple and practicable.

• TCR Haplo-HSCT may have advantages: Engraftment, Lower NRM, rapid immune reconstitution, GVL effect and LFS/OS.

• cGvHD remains to be improved

Conclusion: In-vitro T-cell Depletion is Not Necessary

for Haplo-identical Transplantation

Acknowledgements

Stem cell collection center Hai-Yin Zheng Hong Xu Qing Zhao Su Wang

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

Laboratory of PUIH Dan Li Ya-Zhen Qin Yan-Rong Liu Yue-Yun Lai

35th World Congress of the International Society of

Hematology, 2014

Organized by:

International Society of Hematology

Chinese Society of Hematology

President: Prof. Xiaojun Huang Co-chairs: Prof. Changgeng Ruan Prof. Saijuan Chen General Secretary: Prof. Kaiyan Liu Venue: China National Convention Center, Beijing, China Date: Sept. 4-7, 2014 Congress Website: www.ish2014.org