UNRELATED DONOR TRANSPLANTS
A Bacigalupo,
Ospedale San Martino, Genova, Italy
Donor Safety
5/36317 RELATED
0/14706 UNRELATED
deaths /10.000 donations
BM 27770
PB 23254
death
1
4
2
1,8
1,6
1,4
1,2
1
0,8
0,6
0,4
0,2
0
1,72
0,36
BM
PB
One additional death in Unrelated
Donor
Age =
Gender=
Cause = repiratory insufficiency after
attempted insertion of CVC , and
bilateral pneumothorax
BM 27770
PB 23254
SAE
12
25
SAE /10.000 donations
12
10,76
10
8
6
4,32
4
2
0
BM
PB
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
Preventing acute GvHD II-IV
80
74
70
% of patients
60
56
51
50
40
33
30
23
17
20
10
0
FK+M/ CsA+M
Blood 2000
96:2062
FK+M+S
BBMT 2008;
14:920
C+M+ATG
Lancet Onc 2009:10
C+M+Camp
BJH 2011
march 8
Reduction of GvHD in alternative donor TX
for 402 Myeloid Leukemias: Genova San Martino
80
70
% of patients
60
P<0.0001
69
P<0.0001
58
50
40
<95
<2000
2000+
32
26
30
18
20
10
4
0
GvHD II+
GvHD III-IV
Preventing Chronic GvHD
80
70
76
70
% of patients
60
50
42
47
40
30
20
10
0
FK+M/ CsA+M
Blood 2000
96:2062
FK+M+S
BBMT 2008;
14:920
C+M+Camp
BJH 2011
march 8
% of patients with chronic GvHD
Biol Blood Marrow Transpl ;
2006 ; 12: 560
Chronic GvHD
P<0.0001
70
60
60
50
40
37
41
non ATG
ATG
30
20
15
10
0
Same results with
ATG Thymo
Or
ATG Fresenius
extensive chronic GvHD
% of patients with chronic GvHD
chronic GvHD
Lancet Oncol 2009; 10:855
70
60
P<0.0001
59
50
40
42
non ATG
ATG
31
30
20
12
10
0
chronic GvHD
extensive chronic GvHD
UD or SIB
BM Tx
BU 3.2 mg/kg
x4
Day -7
-6
-5
-4
CY
50
mg
/kg
CY 50
mg/kg
x2
-3
-2
-1
0
+3
CY
50
mg
/kg
+4
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 Disease
Does reduction of GvHD translate in better OS?
OS not significantly different (not inferior) with
ATG vs no ATG
GITMO trial (Thymo)
BBMT 2006; 12:560
German trial (Thymo)
Lancet Onc ; 2009
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 Disease
Does eduction of GvHD translate in better OS?
HLA matching criteria
Worse outcomes with
Any single locus mismatch
n
RR (95% CI)
P-value
Survival
952
1.18 (1.07-1.30)
0.0009
DFS
945
1.16 (1.03-1.31)
0.004
TRM
945
1.34 (1.16-1.54)
<0.0001
Relapse
945
0.90 (0.81-1.00)
0.04
Engraftment
956
OR 0.90 (0.80-1.01) 0.06
Acute GVHD
957
1.38 (1.13-1.63)
0.0008
Chronic GVHD
910
0.96 (0.91-1.03)
0.25
 A single mismatch is associated with worse survival, DFS, TRM,
acute GVHD
Early Stage Disease: Adverse impact of HLA mismatch
HLA-A ,B, C, DR
1,0
0,9
S
u
r
v
i
v
a
l
0,8
8/8 HLA Matched (n=835)
0,7
7/8 HLA Matched (n=379)
0,6
0,5
0,4
0,3
6/8 HLA Matched (n=241)
0,2
0,1
Log-rank p-value = < 0.0001
0,0
0
12
24
36
48
60
Months after transplant
Each mm yield 10-11% worse survival
Lee et al, 2007
Advanced Disease: Limited impact of HLA mismatch
HLA-A ,B, C, DR
1,0
0,9
S
u
r
v
i
v
a
l
0,8
Log-rank p-value = 0.02
0,7
0,6
0,5
8/8 HLA Matched (n=327)
0,4
7/8 HLA Matched (n=195)
0,3
6/8 HLA Matched (n=123)
0,2
0,1
0,0
0
12
24
36
48
Months after transplant
Delay had worse consequences than MMLee et al, 2007
60
Study
Reference
N.patients
Diagnosis
Survival
Type of mismatch
disadvantage in
One should avoid
mismatched pairs
Seattlle
Petersdorf Blood
1249
Leukemia
Early dis
C locus
3860
AML ALL MDS
Early dis
A or DRB1
2004; 104: 2976
NMDP
Lee
CIBMTR
Blood 2007
JMDP
Takakazu
CML
5210
Blood 2007 110;
Malignant and
All patients
non malignant
C locus
Non permissive
2235
mismatches positions
9,77,80,99,116,156
Seattle
Petersdorf
246
Leukemia
All patients
Plos Med 2007; 4:
Haplotype
Mismatched
59
GITMO
Crocchiolo, Blood
537
Leukemia
All patients
2009, 114:1437
CIBMTR
Cooley, Blood 2010,
116:2411
DP non permissive
mismacth
1409
Leukemia
AML
Donor B gene content
<2
KIR genes on Chromosome 19
Segregate indep. From HLA
A group (inhibitory receptors)
B group (activating receptors)
A/A= homozygous for A
B/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 Patients
Mauricette 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:
UD allo-HSCT late registration:
47%
29%
Donor selection
EARLY DISEASE
1.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 DISEASE
The earlier, the better
Donor Registries
Donor Safety
Graft versus Host Disease
Does eduction of GvHD translate in better OS?
HLA matching criteria
Stem 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
Eapen et al, Biol Blood Marrow Transplant, 2007
PBG05_3.ppt
Transplant-Related Mortality
Cumulative Incidence, %
100
80
60
BM (N=781; 46%)
40
PB (N=451; 45%)
20
0
0
12
24
36
Months
Eapen et al, Biol Blood Marrow Transplant, 2007
Relapse
Cumulative Incidence, %
100
80
60
40
PB (N=451; 26%)
20
0
BM (N=781; 24%)
0
12
24
36
Months
Eapen et al, Biol Blood Marrow Transplant, 2007
Leukemia-free Survival
100
Probability, %
80
60
BM (N=781; 31%)
40
PB (N=451; 29%)
20
0
Months: 0
No at Risk
PB: 451
BM: 781
12
24
36
179
306
127
230
48
146
Eapen et al, Biol Blood Marrow Transplant, 2007
Randomized CTN trial (Anasetti et al ASH 2011)
Median follow up 36 months
Peripheral BLOOD
273
MARROW
278
P
Overall survival
OS transplanted
DFS transplanted
51%
52%
47%
46%
48%
44%
0.3
0.3
0.6
Relapse
NRM
ANC 500 day 100
28%
26%
95%
28%
27%
86%
0.8
0,6
0.09
aGvHD II-IV
aGvHD III-IV
47%
16%
46%
14%
0.8
0.3
cGvHD
Ext cGvHD
53%
46%
40%
31%
0.02
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 Registries
Donor Safety
Graft versus Host Disease
HLA matching criteria
Stem cell source
Outcome
ACUTE LEUKAEMIA REGISTRY
ADULTS TRANSPLANTED FROM 2000 TO 2010
MATCHED UNRELATED DONOR / OS at 5 years
AML n=2901
ALL n=1655
50%±1
40%±2
CR1 (n=1117)
CR2 (n=879)
21%±2
ADV (n=905)
46%±2
CR1 (n=804)
28%±2
13%±2
CR2 (n=510)
ADV (n=341)
Matched Unrelated Transplants for SAA
Effect of transplant era
10 year OS
>2000 (752)
(230)
>1980
(27)
1971-80 (1)
67%
44%
29%
0%
Survival Plot >1990
1,000
Survival
0,750
>2000
P<0.0001
1991-00
0,500
1981-90
P=0.1
0,250
1971-80
0,000
0,0
2000,0
4000,0
6000,0
daysDD_FUP
from transplant
8000,0
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 factor
5. Should we continue to use PB??
Donor Registries
WMDA 2012
Activations
2009
2010
44201
46919
BMT Tx
3445 (8%)
3574 (8%)
PB Tx
8162 (18%)
9248 (20%)
CB
3792 (9%)
TOT transpl
15399 (35%)
4036 (9%)
16858 (37%)
REGISTRIES:
Large Donor pool
Searches Activated : UD Transplants
=
44201 : 12822
=
We are transplanting 1/3 of patients who
activate a donor search (optimistically 50%)