UNRELATED DONOR TRANSPLANTS A Bacigalupo, 

Ospedale San Martino, Genova, Italy

Donor Safety

deathBM 27770 1PB 23254 4

5/36317 RELATED

0/14706 UNRELATED

0,36

1,72

00,20,40,60,8

1

1,21,41,61,8

2

BM PB

deat

hs /1

0.00

0 do

nati

ons

One additional death in Unrelated Donor

Age =Gender=Cause = repiratory insufficiency after attempted insertion of CVC , and bilateral pneumothorax

SAEBM 27770 12PB 23254 25

4,32

10,76

0

2

4

6

8

10

12

BM PB

SAE

/10.

000

dona

tion

s

DONOR SAFETY

1.HSC donations carries a small, but proven hazard: we must be cautious (VERY) in selecting HSC donor

2. PB donations are not safer than BM Higher death rate and signficantly higher SAE rate for

PB vs BM donations. Informed consent should say so

3. Accurate donor screening will reduce risk of lethal complications

Lower death risk occurred in UNRELATED donations

Donor Safety Graft versus Host Disease

56

17

51

23

74

33

0

10

20

30

40

50

60

70

80

FK+M/ CsA+M FK+M+S C+M+ATG C+M+Camp

% o

f pa

tien

tsPreventing acute GvHD II-IV

Blood 2000    BBMT 2008; BJH 201196:2062     14:920            Lancet Onc 2009:10 march 8

69

32

58

18

26

4

0

10

20

30

40

50

60

70

80

GvHD II+ GvHD III-IV

% o

f pa

tien

ts

<95<20002000+

Reduction of GvHD in alternative donor TX for 402 Myeloid Leukemias: Genova San Martino

P<0.0001

P<0.0001

76

4247

70

0

10

20

30

40

50

60

70

80

FK+M/ CsA+M FK+M+S C+M+Camp

% o

f pa

tien

tsPreventing Chronic GvHD

Blood 2000    BBMT 2008; BJH 201196:2062     14:920            march 8

60

4137

15

0

10

20

30

40

50

60

70

chronic GvHD extensive chronic GvHD

% o

f p

atie

nts

wit

h c

hro

nic

GvH

D

non ATGATG

Biol Blood Marrow Transpl ; 2006 ; 12: 560

59

42

31

12

0

10

20

30

40

50

60

70

chronic GvHD extensive chronic GvHD

% o

f p

atie

nts

wit

h c

hro

nic

GvH

D

non ATGATG

Lancet Oncol 2009; 10:855

Same results withATG Thymo OrATG Fresenius

Chronic GvHD

P<0.0001

P<0.0001

Day -7 -6 -5 -4 -3 -2 -1 0 +3 +4

BU 3.2 mg/kgx4

CY 50 mg/kg

x2

UD or SIBBM Tx

CY 50 mg/kg

CY 50 mg/kg

GvHD

1.Prophylaxis with 2 drugs (C+M, T+M) is associated with significant acute+chronic GvHD

2. A third agent (ATG or CAMPATH or SIROLIMUS) signifanctly REDUCES acute +GvHD

3. ATG significantly reduces chronic GvHD

4. High dose CY post-Transplant may be a promising new option

with or without C+M

Donor Safety Graft versus Host DiseaseDoes reduction of GvHD translate in better OS?

GITMO trial (Thymo)BBMT 2006; 12:560

German trial (Thymo)Lancet Onc ; 2009

OS not significantly different (not inferior) with ATG vs no ATG

Very long follow up (over 10 years) , may allow for late complications of chronic GvHD (in particular lung complications) to become clinically relevant

Donor Safety Graft versus Host DiseaseDoes eduction of GvHD translate in better OS?HLA matching criteria

Any single locus mismatchAny single locus mismatch

0.00081.38 (1.13-1.63)957Acute GVHD

0.250.96 (0.91-1.03)910Chronic GVHD

0.06OR 0.90 (0.80-1.01)956Engraftment

0.040.90 (0.81-1.00)945Relapse

<0.00011.34 (1.16-1.54)945TRM

0.0041.16 (1.03-1.31)945DFS

0.00091.18 (1.07-1.30)952Survival

P-valueRR (95% CI )n

A single mismatch is associated with worse survival, DFS, TRM, acute GVHD

Worse outcomes with

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0 12 24 36 48 60

Survival

Log-rank p-value = < 0.0001

8/ 8 HLA Matched (n=835)

7/ 8 HLA Matched (n=379)

Months after transplant

6/ 8 HLA Matched (n=241)

Early Stage Disease: Adverse impact of HLA mismatch

HLA-A ,B, C, DR

Lee et al, 2007Each mm yield 10-11% worse survival

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0 12 24 36 48 60

Survival

Log-rank p-value = 0.02

8/ 8 HLA Matched (n=327)

7/ 8 HLA Matched (n=195)

Months after transplant

6/ 8 HLA Matched (n=123)

Advanced Disease: Limited impact of HLA mismatch

HLA-A ,B, C, DR

Lee et al, 2007Delay had worse consequences than MM

Study Reference N.patients Diagnosis Survival

disadvantage in

mismatched pairs

Type of mismatch

One should avoid

Seattlle Petersdorf Blood

2004; 104: 2976

1249 Leukemia Early dis C locus

NMDP

CIBMTR

Lee

Blood 2007

3860 AML ALL MDS

CML

Early dis A or DRB1

JMDP Takakazu

Blood 2007 110;

2235

5210 Malignant and

non malignant

All patients C locus

Non permissive

mismatches positions

9,77,80,99,116,156

Seattle Petersdorf

Plos Med 2007; 4:

59

246 Leukemia All patients Haplotype

Mismatched

GITMO Crocchiolo, Blood

2009, 114:1437

537 Leukemia All patients DP non permissive

mismacth

CIBMTR Cooley, Blood 2010,

116:2411

1409 Leukemia AML Donor B gene content

<2

KIR genes on Chromosome 19Segregate indep. From HLA

A group (inhibitory receptors)B group (activating receptors)

A/A= homozygous for AB/x (at least one B)

Lancet February 15, 2012

HLA 10/10 match

DP permiss mm# same TRM as DP=# lower TRM as DP non perm mm# lower Relapse as DP=

V

V

Faster Registration on International Donor Registries and Shorter Time to Allogeneic Hematopoietic Stem Cell Transplantation After Having Found a Donor Confers Better Outcome In Acute Leukemia PatientsMauricette Michallet1, Lyon Abstract 2371 ASH 2010;

Patients = 251 with acute leukemia and active donor search 2000-2008

The 3years OS for SD allo-HSCT 59%UD allo-HSCT early registration: 47%UD allo-HSCT late registration: 29%

Donor selection

EARLY DISEASE1.Choose 8/8 = A,B,C,DRB1 donors

2. permissive DP mm should be preferred of non permissive mm

3.In AML patients , if possible, with a NK -B cent haplotype

ADVANCED DISEASEThe earlier, the better

Donor RegistriesDonor Safety Graft versus Host DiseaseDoes eduction of GvHD translate in better OS?HLA matching criteriaStem cell source

Patient Selection Transplants in 2000-2003 PB = 451 BM = 781 Age, 18-60 yrs ALL, AML, MDS and CML   Excluded:

T-cell depleted grafts Reduced Intensity Conditioning

Median follow-up:  PB, 34 months BM, 38 months

PBG05_3.ppt

Eapen et al, Biol Blood Marrow Transplant, 2007

Months

Cu

mu

lati

ve I

ncid

en

ce,

%

100

0

20

40

60

80

0 3612 24

PB (N=451; 45%)

BM (N=781; 46%)

Transplant-Related Mortality

Eapen et al, Biol Blood Marrow Transplant, 2007

Months

Cu

mu

lati

ve I

ncid

en

ce,

%

100

0

20

40

60

80

0 3612 24

BM (N=781; 24%)

PB (N=451; 26%)

Relapse

Eapen et al, Biol Blood Marrow Transplant, 2007

Pro

bab

ilit

y, %

100

0

20

40

60

80

PB (N=451; 29%)

BM (N=781; 31%)

Months: 0 12 24 36No at Risk PB: 451 179 127 48

BM: 781 306 230 146

Leukemia-free Survival

Eapen et al, Biol Blood Marrow Transplant, 2007

Randomized CTN trial (Anasetti et al ASH 2011)Median follow up 36 months

Peripheral BLOOD MARROW P273 278

Overall survival 51% 46% 0.3OS transplanted 52% 48% 0.3DFS transplanted 47% 44% 0.6

Relapse 28% 28% 0.8NRM 26% 27% 0,6ANC 500 day 100 95% 86% 0.09

aGvHD II-IV 47% 46% 0.8aGvHD III-IV 16% 14% 0.3

cGvHD 53% 40% 0.02Ext cGvHD 46% 31% 0.01

Stem cell source

1.Same TRM /relapse / LFS

2.More chronic GvHD

Both in retrospective and prospective trials

PERIPHERAL BLOOD TRANSPLANTS

DONORS# more SAE for PB donations (significant)# more deaths (ns) # should be stated in the informed consent

PATIENTS# no protection against relapse# same TRM; same LFS # more chronic GvHD

Should we continue to use PB grafts routinely? ??

Donor RegistriesDonor Safety Graft versus Host DiseaseHLA matching criteriaStem cell sourceOutcome

ACUTE LEUKAEMIA REGISTRY

ADULTS TRANSPLANTED FROM 2000 TO 2010MATCHED UNRELATED DONOR / OS at 5 years

AML n=2901 ALL n=1655

50%±1

40%±2

21%±2

46%±2

28%±2

13%±2

CR1 (n=1117)

CR2 (n=879)

ADV (n=905)

CR1 (n=804)

CR2 (n=510)

ADV (n=341)

Matched Unrelated Transplants for SAAEffect of transplant era

0,000

0,250

0,500

0,750

1,000

0,0 2000,0 4000,0 6000,0 8000,0

Survival Plot

DD_FUP

Su

rviv

al

10 year OS >2000 (752) 67%>1990 (230) 44%>1980 (27) 29%1971-80 (1) 0%

P=0.1

P<0.0001

>2000

1991-00

1971-80

1981-90

days from transplant

Conclusions

1.Caution required for donor harvest (BM and especially PB)

2.Several options for HLA /non HLA donor selection

3.Three agents (C+M+other) for appropriate GvHD prophylaxis

4.Time to transplant= crucial factor5. Should we continue to use PB??

Donor Registries

2009 2010

Activations 44201 46919

BMT Tx 3445 (8%) 3574 (8%)

PB Tx 8162 (18%) 9248 (20%)

CB 3792 (9%) 4036 (9%)

TOT transpl 15399 (35%) 16858 (37%)

WMDA 2012

REGISTRIES:

Large Donor poolSearches Activated : UD Transplants=44201 : 12822=

We are transplanting 1/3 of patients who activate a donor search (optimistically 50%)