unrelated donor transplants a bacigalupo, ospedale san martino, genova, italy
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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%)
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