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Haploidentical Stem cell Transplantation. Tsila Zuckerman Rambam Health Campus ISH 5/2009. Topics for discussion. Principles of haplo transplants Update data on haplo SCT( OS,DFS,TRM) Future directions (Improving results) in haplo (CTLs, T replete , NIMA) Pro & cons.

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haploidentical stem cell transplantation

Haploidentical Stem cell Transplantation

Tsila Zuckerman

Rambam Health Campus

ISH 5/2009

topics for discussion
Topics for discussion

Principles of haplo transplants

Update data on haplo SCT( OS,DFS,TRM)

Future directions (Improving results) in haplo (CTLs, T replete , NIMA)

Pro & cons

principles of haplo sct
Principles of Haplo SCT
  • Virtually every patient has a potential haplo donor.
  • Major historical obstacles in 3 loci mismatched transplant:

Lethal GVHD

Graft rejection

slide4

The veto effect

Veto activity is the capacity of the donor CD34 + cells

to specifically suppress

host CTL-p directed against antigens of the veto cells themselves

Reich-Zeliger et al. 2004

J. Immunol. 173:6660

principles of haplo transplants
Principles of Haplo Transplants
  • High intensity conditioning for maximal anti tumor effect & immunosupression
  • “Megadose” of stem cells to insure engraftment
  • Extensive T cell depletion to prevent GVHD
  • No post transplant immunosupression to facilitate immune reconstitution
update data on haplo sct
Update Data on Haplo SCT

Perugia experience:

Use of automated clinimacs device with increased yield of CD34 cells collection, median reduction of T cells of 4.5 logs and B cells of 3.2 log.

104 patients .

67 AML, 30% in relapse.

37 ALL, 35% in relapse.

engraftment :primary 94%,secondary 100%.

a GVHD II-IV 2%,cGVHD ext. 4%.

TRM 36.5%. 70% due to infections (>50% viral)

1104 patients .

Aversa F. JCO 2005

slide7

Probability of EFS according to disease status at transplantation

Primary engraftment 94%

Secondary engraftment 100%

aGVHD II-IV 2%

cGVHD 4%

TRM 36.5%( 70% infection related)

Aversa F. et al. J Clin Oncol; 2005

slide8

Cumulative incidence of leukemia relapse at 2 years for patients with ALL & AML according to disease status at transplantation

Aversa F. et al. J Clin Oncol, 2005

slide9

EBMT Survey on Haplo BMT

Leukemia free survival according to disease status

173 AML

93 ALL

Ciceri F et al, Blood 2008

slide10

EBMT Survey on Haplo BMT

Relapse rate according to disease status

Ciceri F et al, Blood 2008

slide12

NK cells alloreactivity

  • Lack of expression of self MHC molecules on mismatched allogeneic targets results in NK cell mediated lysis (“missing self” recognition)
slide13

Balance between activating and inhibitory receptors

Regulation of NK cell response by activating and inhibitory receptors

slide15

Relapse rate according to the presence of NK alloreactivity & disease status at transplantation

112 high risk AML

61 CR

51 relapse

Ruggeri, L. et al. Blood 2007

slide16

OS according to NK alloreactivity status

Ruggeri, L. et al. Blood 2007

susceptibility to nk alloreactivity
Susceptible

T- ALL

AML

CML

NHL

MM

Resistant

common phenotype ALL

Susceptibility to NK alloreactivity
new modalities in haplo transplants
New modalities in Haplo transplants
  • Reduced intensity transplants
  • T replete transplants
  • Choosing the right donor (feto- maternal microchimerisem)
  • Enhancing GVL effect (DLI / NK infusion)
  • Immune reconstitution
new modalities in haplo transplants1
New modalities in Haplo transplants
  • Reduced intensity transplants
  • T replete transplants
  • Choosing the right donor (feto- maternal microchimerisem)
  • Enhancing GVL effect (DLI / NK infusion)
  • Immune reconstitution
new modalities in haplo transplants2
New modalities in Haplo transplants
  • Reduced intensity transplants
  • T replete transplants
  • Choosing the right donor (feto- maternal microchimerisem)
  • Enhancing GVL effect (DLI / NK infusion)
  • Immune reconstitution
t replete transplants
T replete transplants

Luznik L Biol Blood Marrow Transpl. June , 2008

t replete transplants1
T replete transplants

N=68

Luznik L Biol Blood Marrow Transpl. , 2008

slide24

Transplant outcome

Luznik L Biol Blood Marrow Transpl., 2008

new modalities in haplo transplants3
New modalities in Haplo transplants

Reduced intensity transplants

T replete transplants

Choosing the right donor (feto- maternal microchimerisem)

Enhancing GVL effect (DLI / NK infusion)

Immune reconstitution

haplo sct from tolerized donor
Haplo SCT from Tolerized Donor

Tolerance induced from in uterore exposure to maternal Ags and results in long lasting feto-maternal microchimerism.

Tolerized donor: mother or NIMA mismatched sibling.

slide27

Proposed scheme for choosing the appropriate donor

PARENTSHAPLOIDENTICAL Sib

Mother

NIMA / IMA

c b

(1)

NIMA / IPA

a d

Patient

IMA / IPA

b d

Father

NIPA / IPA

c d

(2)

NIPA / IMA

c b

slide28

Haploidentical SCT

T-cell-replete NIMA-complementary SCT (n=35)

aGVHD II-IV

aGVHD III-IV

OS

OS

Ichinohe T et al: Blood 2004

slide29

aGVHD grade II-IV following mismatched related transplant according to donor type

IBMTR registry study

269 patients with acute leukemia

Family donor 1-2 Ag mismatch

P<0.02

Jon j. van Rood ,Blood 2002

new modalities in haplo transplants4
New modalities in Haplo transplants

Reduced intensity transplants

T replete transplants

Choosing the right donor (feto- maternal microchimerisem)

Enhancing GVL effect (DLI / NK infusion)

Immune reconstitution

enhancing gvl effect dli nk infusion
Enhancing GVL effect (DLI / NK infusion)
  • G-CSF mobilized DLI (1x106/ kg) with short course immunosupressionHuang XJ ,JCI,2008,28(4):390-7
  • CD8 depleted DLI . Soiffer RJ, Biol Blood Marrow Transplant,2002,8(11) 625-32.
  • NK- DLI ( ≥ 1.0 x 10(7)/kg CD56+/CD3- NK cells)Passweg JR, Leukemia,2004,18: 1835-1838
new modalities in haplo transplants5
New modalities in Haplo transplants

Reduced intensity transplants

T replete transplants

Choosing the right donor (feto- maternal microchimerisem)

Enhancing GVL effect (DLI / NK infusion)

Immune reconstitution

immune reconstitution
Immune reconstitution
  • Suicide gene engineered DLI . Ciceri F , lancet oncol,2009,10(5);489-500
  • Adoptive transfer of virus specific (CMV,EBV) cytotoxic T lymphocytes Peggs K, lancet,2003,362,1375-1377
  • Selective depletion of alloreactive T cells using immunotoxins, immunomagnetic beads, FACs sorting, photodynemic purgingPerruccio K , Blood Cells Mol Dis. 2008 Jan-Feb;40(1):76-83.
slide37

EUROCORD

Comparison of outcomes after

Unrelated Cord Blood or

Haploidentical T-cell depleted Peripheral Blood Stem Cells in Adults with High Risk Acute Leukemia

V Rocha, F Aversa, M Labopin, G Sanz, F Ciceri, W Arcese, D Bunjes, J Rowe, P Di Bartolomeo, F Frassoni, M Martelli and E Gluckman on behalf of the Eurocord-Netcord and Acute Leukemia Working Party EBMT

slide38

Patients

From 1998-2002

229 haplo and 139 UCBT were performed for adults with high risk acute leukemia (AML and ALL)

Two different analysis were performed:

AML patients Haplo= 154

UCBT= 66

ALL patients Haplo= 75

UCBT= 73

slide39

AML Patients and Disease characteristics

Haplo UCBT P

N 154 66

Status at transplant 0.9

CR1 33 (21%) 15 (23%)

CR2 32 (21%) 12 (18%)

More advanced 89 (58%) 39 (59%)

Previous autologous transplant 21% 25% 0.61

Intervalfromdiag-transplant 333 d 384 d 0.16

Medianyear of transplantation 2000 2000 0.21

slide40

1.0

Haplo versus UCBT for adult patients with AML

LFS

.8

.6

UCBT (n=66)

30±6%

.4

.2

Haplo (n=154)

24±4%

P=0.39

years

0.0

3

0

1

2

slide41

1.0

Haplo versus UCBT for adult patients with ALL

LFS

.8

.6

CB (n=73)

36±6%

.4

.2

Haplo (n=75)

13±4%

P=0.01

years

0.0

0

1

2

3

slide42

Overall survival of MRD , Haplo and MUD

according to disease status (early vs late)

Early

Δ= MRD

●=MUD

=haplo

Late

◊=MRD

▼=MUD

▲=haplo

Ottinger HD, Blood 2003

slide43

□ - MRD

Δ – haplo

▼ - MUD

Ottinger HD et al, Blood 2003

slide44

Relapse risk

Adv MRD

Adv MUD

Early MRD

Adv Haplo

Early Haplo

Early MUD

Ottinger HD et al, Blood 2003

pro cons
Pro

Donor for every patient

Immediate availability

Ability to select the best of many potential donors

Easy access to repeat donation/DLI

Cons

Delayed immune reconstitution

Pro & cons