slide1
Download
Skip this Video
Download Presentation
Cord Blood v s. Unrelated Donor Transplantation Elizabeth J. Shpall , MD

Loading in 2 Seconds...

play fullscreen
1 / 37

Cord Blood v s. Unrelated Donor Transplantation Elizabeth J. Shpall , MD - PowerPoint PPT Presentation


  • 139 Views
  • Uploaded on

Cord Blood v s. Unrelated Donor Transplantation Elizabeth J. Shpall , MD. Allogeneic Marrow Transplantation. Treatment of choice for selected high-risk patients with: Acute Leukemia (ALL, AML) Chronic Leukemia (CML, CLL) Follicular Lymphomas Aplastic Anemia

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' Cord Blood v s. Unrelated Donor Transplantation Elizabeth J. Shpall , MD' - glenys


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
slide1

Cord Blood vs. Unrelated Donor

Transplantation

Elizabeth J. Shpall, MD

slide2

Allogeneic Marrow Transplantation

  • Treatment of choice for selected high-risk patients with:
  • Acute Leukemia (ALL, AML)
  • Chronic Leukemia (CML, CLL)
  • Follicular Lymphomas
  • Aplastic Anemia
  • Several Genetic and Immunologic Diseases
  • Less than 30% of patients have a related donor
  • Increasing use of unrelated and cord blood donors
slide3

Potential Advantages of Cord Blood

  • Procurement non-invasive
  • Expanded donor pool: minorities targeted
  • Immediate availability (overnight shipping)
  • Requires less stringent HLA matching(4/6, 5/6)
  • Less GVHD than marrow transplants
slide5

M. D. Anderson BMT Department

Minority Allo-transplants by Stem Cell Source

59%

25%

N=3038

Bone marrow

Peripheral blood

Transplants

Year 1980 - 2003

N=280

Cord blood transplants

Year 1996 - 2010

slide6

Outcomes after Transplantation of Cord Blood or Bone Marrow

from Unrelated Donors in Adults with Acute Leukemia

Eurocord data compared to EBMTR

data on MUD bone marrow transplants

Cord blood n = 98

Bone marrow n = 584

HLA matching

Cord blood: 94% with at least one mismatch

Bone marrow: 100% matched

Median cell dose

Cord blood: 0.23 x 108

Bone marrow: 2.9 x 108

Rocha, V. et al. N Engl J Med 2004;351:2276-2285

slide8

MyeloablativeCBT

For AML/ ALL

(CR1/ 2):

Survival

Relapse

1.0

0.8

p = 0.05

0.6

Single 30% (16 - 44%)

0.4

Double 9% (0 - 21%)

0.2

1.0

0.0

0

4

8

12

16

20

24

Months

I

I

I

0.8

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

Doubles (n = 29) 72% (56 - 88%)

0.6

Probability

I

I

I

I

I

I

I

I

Singles (n = 67) 47% (51-75%)

0.4

0.2

p = 0.16

0.0

0

1

2

3

Years

Verneris et al, Blood 2005, 106; 93a

non myeloablative conditioning
Non-Myeloablative Conditioning

Cyclosporine

Tacrolimus

Tacrolimus

Tacrolimus

Sirolimus

MMF

Fludarabine 30 mg/m2/d ATG 1.5 mg/kg/d Melphalan 100 mg/m2/d

slide10

1.0

0.8

I

I

I

45%

(95%CI 36-54)

I

I

I

I

I

I

I

I

I

0.6

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

Cumulative Proportion

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

0.4

0.2

0.0

0

1

2

3

4

5

Years

Promising Overall Survival after

NonmyeloablativeCB Transplantation

Brunstein et al. Blood 2007

slide11

Methods-Eapen et al

  • Explored whether there were survival differences by conditioning regimen within each graft source:
    • survival after dCB with TBI200/Cy/Flu ± ATG vs. dCB with other regimens
    • No differences in the PB group
  • Therefore 4 treatment groups were created:
    • MUD (8/8 allele matched unrelated donor)
    • MMUD (7/8 allele matched unrelated donor)
    • dCB, TCF
    • dCB, other
slide15

100

100

90

90

80

80

70

70

60

60

50

50

40

40

30

30

20

20

10

10

0

0

Neutrophil Recovery

MUD: 96%

MMUD: 95%

dCB, TCF: 83%

Cumulative Incidence, %

dCB, other: 83%

P=0.0007

0

7

14

21

28

35

42

Days

Fk10_54.ppt

slide16

100

100

90

90

80

80

70

70

60

60

50

50

40

40

30

30

20

20

10

10

0

0

Platelet Recovery

MUD: 90%

MMUD: 89%

dCB, TCF: 66%

Cumulative Incidence, %

dCB, other: 58%

P <0.0001

0

1

2

3

4

5

6

Months

Fk10_53.ppt

slide17

100

100

90

90

80

80

70

70

60

60

50

50

40

40

30

30

20

20

10

10

0

0

Grade 3-4 Acute GVHD

P=NS

Cumulative Incidence, %

dCB, TCF: 17%

MMUD: 22%

dCB, other: 18%

MUD: 13%

0

1

2

3

4

5

6

Months

Fk10_51.ppt

slide18

100

100

90

90

80

80

70

70

60

60

50

50

40

40

30

30

20

20

10

10

0

0

Chronic Graft vs. Host Disease

P<0.0001

MUD: 56%

Cumulative Incidence, %

MMUD: 54%

dCB, other: 36%

dCB, TCF: 34%

0

6

12

18

24

30

36

Months

Fk10_50.ppt

slide19

100

100

90

90

80

80

70

70

60

60

50

50

40

40

30

30

20

20

10

10

0

0

Leukemia-Free Survival

P=0.017

Probability, %

dCB, TCF: 26%

MUD: 31%

MMUD: 25%

dCB, other: 9%

0

6

12

18

24

30

36

Months

Fk10_49.ppt

slide20

Double CBT LFS is comparable to MRD and MUDFred Hutchison Ca Center and Univ Minnesota

P<0.01

P=NS

MRD p<0.01

MUD p=0.13

MMUD p<0.01

N=536

CBT 128

MRD 204

MUD 152

MMUD 52

Brunstein and Delaney, Blood 2010

slide21

Disadvantages of Cord Blood vs. Bone Marrow or Peripheral Blood Progenitor Cell (PBPC)

Transplantation

  • Low Cell Dose
  • Delayed Engraftment
  • Delayed Immune Reconstitution
  • Increased Graft Failure
  • PBPC remains the “gold standard” against which performance of CB compared:
  • Neutrophil engraftment (>500/µl) 11 days
  • Platelets engraftment (>20,000/µl) 13 days
  • Engraftment failure rate <1%
slide22

Mesenchymal Stem Cells (MSC)

  • MSC are a stromal component
  • of the hematopoietic microenvironment.
  • They provide cellular and extracellular components of the stem cell “niche”.
  • When isolated and used in vitro
  • in combination with cytokines, MSC markedly increase the expansion of CB hematopoietic progenitors.
slide23

M. D. Anderson CB Expansion Trial with

“off-the-shelf” Angioblast MPC (N=24)

Single vial of

Angioblast MSC

Frozen

CB unit

Day 14:

Non-adherent cells washed and infused

CB MNC

thawed

and

washed

Day 7-14 culture

SCF

G-CSF

Flt-3L

TPO

1 liter

10 bags

T150

Day 1- 7 co-culture

10 flasks

+

4 days

14 day ex vivo expansion culture

slide24

MSC-CB Expansion Trial

Day 0

Infuse unmanipulated CB unit

AND

Ex vivo expanded CB unit

GvHD Prophylaxis:

Tacrolimus and MMF

slide25

MSC-CB Expansion Trial Engraftment Data

Median time to engraftment (range)

Neutrophil (>500/µl) 15 days (range 9-42)

Platelet (>20,000/µl) 40 days (range 13-62)

Cumulative Incidence of Engraftment

Neutrophil (>500/µl) 97% (n=31)

Platelet (>20,000/µl) 81% (n=26)

- One patient died before engraftment

de Lima et al. Blood (ASH Annual Meeting Abstracts), 2010; 116: 362

slide26

Cumulative Incidence of Neutrophil Recovery

100

80

Angioblast

(@26 days, 88%, N=24)

60

Cumulative Incidence (%)

CIBMTR

(@26 days, 53%, N=80)

40

20

@26 days

P<0.0001

0

0

6

12

18

24

30

36

42

Days after Transplant

M. Horowitz et al.

slide27

Cumulative Incidence of Platelet Recovery

100

@26 days

P=0.0008

80

60

Cumulative Incidence (%)

Angioblast

(@60 days, 67%, N=24)

40

20

CIBMTR

(@60 days, 31%, N=80)

0

0

6

12

18

24

30

36

42

48

54

60

Days after Transplant

M. Horowitz et al.

slide28

Obstacles to Successful Outcomes after Cord Blood Transplantation: GVHD

  • Potential Solution:
  • Cord Blood Regulatory T cells (Tregs) co-expressing CD4/CD25 have been shown to inhibit alloreactive T cell function
  • We hypothesized that prophylactic infusion of 3rd party CB Tregs would abrogate GVHD
slide29

CD4+25+ CB cells isolated magnetically and cultured with IL2 and

  • Xcyte Bead CD3/28 co-expression (cell: bead=1:3) or
  • Clone 4 K562-APCs (cell:bead=1:4)

OKT3

IL-15

CD64

CD69

CD187c

APC

Parmar et al.

CD86

slide31

Ex vivo expanded CB Tregs reduce GVHD and enhance survival in mice

Log rank test

Treg+PBMC

p < 10-4

PBMC alone

Parmar et al.

Days post Transplant

slide32

NO Treg

WITH Treg

LUNG

LIVER

Recipients of Tregs do not show signs of GVHD – Parmar et al.

A clinical trial with CB Tregs is being designed

NO Treg

WITH Treg

slide33

Obstacles to Successful Outcomes after Cord Blood Transplantation: Relapse

  • Large granular lymphocytes, comprising 10-15% of all peripheral blood lymphocytes
  • CD56+CD3-
  • Have the ability to directly kill target cells in an MHC-independent manner
  • GVL without GVH
slide35

CB-derived NK Cells can kill Primary CLL

Cells in vitro – Bollard Laboratory

slide36

Specific cell populations will be generated in the GMP Lab:

Tumor-

Specific

CB NK

cells

Viral-Tumor

Specific

CB

T cells

CB#2

CB#1

B Cell

Myeloid

Tumors

CB Tregs

MSC-Expansion +/- FTVI

for neut and plat engraftment

AdenoCMV

EBV

-6

-5

-4

-3

-2

-1

0

30

100

Future Directions: Cord Blood Transplantation in the Next 5 Years

slide37

Acknowledgements

Richard Champlin Marcos de Lima Elizabeth Shpall

Laurence Cooper Frank Marini John McMannis

Simrit Parmar Chitra Hosing Nina Shah

Borje Andersson Michael Andreeff Simon Robinson

Steven Kornblau Sergio Giralt Hong Yang

Roy Jones Peter Thall Dongxia Xing

Martin Korbling Paolo Anderlini William Decker

Amin Alousi Issa Khouri Michael Thomas

Naoto Ueno Jeffrey Molldrem Patrick Zweideler

Partow Kebriaei Muzaffar Qazilbash Tara Sadeghi

Laura Worth Demetri Petropoulos Indreshpal Kaur

Mark Munsell Marcelo Fernandez-Viña Sufang Li

Jingjing Ng Ping Fu Jared Burks

Doyle Bosque Lori Griffin Susan Kelly

Gabriela Rondon Rima Saliba Sufira Kiran

Catherine Bollard

Gianpietro Dotti

Ann Leen

Barbara Savoldo

Mary Horowitz

Mary Eapen

Funding

NCI : R01- CA061508

NCI : PO1- CA148600

CPRIT: RP100469

CPRIT: RP 100430

CLL Global Research Found

HRSA: 234200737

Ian McNiece

Krishna Komanduri

Paul Simmons

Natalie Brouard

ad