Transcript Greffe de sang de cordon ombilical

Greffe de sang de cordon
ombilical
An update on the management of
haematological malignancies
Tunis, octobre 2010
Hematopoietic reconstitution in a patient with Fanconi's anemia by
means of umbilical cord blood from an HLA-identical sibling
Gluckman E, Broxmeyer HE, Auerbach AD, Freidman HS, Douglas GW,
Devergie A, Esperou H, Thierry D, Socié G, Lehn P, Cooper S, English D,
Kurtzberg J, Bard J, Boyse EA.
N Engl J Med 1989;321:1174-1178
Développement des greffes de sang de cordon ombilical
1988
1ere greffe mondiale à Paris, Hôpital Saint Louis
1992-93
Développement de banques non apparentées
1993-95
Les greffes HLA incompatibles chez l’enfant
1995
Etablissement d’Eurocord Netcord
1997
Critères de choix des donneurs: la dose cellulaire avant le HLA
1998
Larges séries rétrospectives confirmant les succès dans diverses
maladies
>2000
Résultats comparables moelle et cordon chez l’enfant
2002
Utilisation chez l’adulte
2004
Double greffes et conditionnement non myéloablatif chez l’adulte
2004-05
Isolement de cellules souches non hématopoïétiques
2004-05
Résultats comparables moelle et cordon chez l’adulte
2006
Augmentation du nombre de greffes de sang de cordon. Plus
d’adultes que d’enfants greffés
2007
Recherches sur la médecine régénérative
Avantages du sang de cordon
Rapidement disponible
Pas de délai pour organiser
la greffe
– Typage HLA
– Recherche virale
– Pas de risque pour le
donneur
Pas de problèmes éthiques
Development of public cord blood banks
Figure 2: Total Number of cord blood units available for
transplantation
Number of cord blood units
(x thousand)
452
450
406
400
350
292
300
250
229
136
150
105
100
50
256
181
200
44
70
0
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Year
2004
Year
units provided
2005
2,086
1,791
2003
2006
2,825
2002
2,743
2001
1,126
2000
963
617
1999
540
3,000
2,750
2,500
2,250
2,000
1,750
1,500
1,250
1,000
750
500
250
0
390
Figure 2: Number of cord blood units provided for
unrelated transplantation
368
WMDA 2009
500
Number of cord blood units
• Better selection of patients
and timing of transplant.
• Improvement of clinical
protocols
• Better selection of CB units
(HLA and NC)
• Increase on High Quality CB
units availability
•More than 400.000 units
stored and more than 20.000
units transplanted
2007
2008
EUROCORD
Number of CBT by year
Unrelated CBT according to
reported to Eurocord
recipient age by year
Related
Children n=3287
n=596
Unrelated n=6140
Adults n=2770
1000
600
900
800
500
700
400
600
500
300
400
200
*
100
2010
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
0
1997
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
0
1996
100
1995
200
*
1994
300
*Still collecting data
EUROCORD
Reduced intensity Conditioning
before UR CBT/year n=1516
Double UR CBT/ year
n=1080
232
250
287
300
248 245
246
255
250
211
185
200
200
152
150
150
99
100
39
50
2
0
2
3
6
10
*
100
39 46
50
9
4
9
15
9
17 16
55
70
84
*
1
0
*Still collecting data
Indications by diagnosis
Children
Adults
Greffes de sang de cordon: les acquits
• Peut remplacer la greffe de moelle osseuse dans toutes ses
indications avec des résultats équivalents chez l’adulte comme
chez l’enfant
• Indications:
–
–
–
–
–
Leucémies aigues et chroniques
Lymphomes, myélomes
Aplasies médullaires
Hémoglobinopathies
Maladies héréditaires de la moelle osseuse
Greffe de sang de cordon ombilical: Progrès
• Développement des banques de sang de cordon
• Critères de sélection des donneurs en fonction du
nombre de cellules , du HLA et du diagnostic
• Comparaison des résultats avec les autres sources
de cellules souches hématopoiétiques
• Nouvelles méthodes de facilitation de prise de la
greffe
• La médecine régénérative
What did we learn from the clinical studies
• Engraftment is delayed and depends on number of CD34+ cells in the
graft
optimal dose >2x105/kg
• GVH is reduced
• GVL is functional
• Immune reconstitution is delayed
• Long term survival is improved because of the better quality of
hematologic and immunologic reconstitution
Aujourd’hui
Trouver un donneur n’est plus un problème, le problème est de
faire le bon choix entre
Cordon
simple ou
double
20%fratrie
HLA
identique
35% HLA
identique de
moelle non
apparenté
geno id
non apparenté
no donor?
UCBT malignant disorders (n=925)
0.6
0.4
3-4 differences
2 differences
0.2
0-1 difference
P=0.99
0.0
Event-Free Survival
0.8
1.0
Disease-free survival according to number of HLA
0
20
40
60
Months
80
100
Principaux critères pour la recherche et l’identification d’une
source alternative de cellules souches hématopoïétiques
UBMT
UCBT
Haplo-HSCT
16 – 56
~ 80
100
3–6
<1
immédiate
Donneurs identifiés, mais pas disponibles(%)
20 – 30
~1
Non
Haplotypes rares (%)
2 – 10
20
-
HLA
Dose cellulaire
Difficile
Facile
Facile
Potentiel pour immunotherapie
Oui
Non
Oui (limité)
Potentiel de transmission virale
Oui
Non
Oui
Potential de transmission de maladie cong.
Non
Oui
Non
Risque pour le donneur
Bas
Non
GvHD
Rejet, délai de
reconstitution
immunitaire
Bas
délai de
reconstitution
immunitaire, pas
d’effet GvL (Tcell)
Information sur le typage A, B, DRB1 (%)
Délai médian de recherche (mois)
Limite principale
Possibilité de changer la date de greffe
Problèmes principaux à resoudre
Grewal et al, Blood 2003 - Rocha et Locatelli, BMT 2008
Mobilisation cell.
Probabilité ajuste de survie sans leucémie
Survie sans leucémie après greffe non apparentée chez les enfants
avec leucémie aigue selon la source de cellules
100
CB matched (n=35) 60%
CB 1-Ag MM high (n=157) 45%
BM matched (n=116) 38%
80
60
40
CB 2-Ag MM (n=267) 33%
CB 1-Ag MM low (n=44) 36%
20
0
0
12
24
Mois
36
48
60
Eapen et al, Lancet 2007
Eapen et al, Lancet 2007
EUROCORD survie comparée moelle et cordon
chez les adultes avec une leucémie aigue
1.0
Survie sans leucémie
.8
.6
35 %  2
.4
32 %  6
.2
P (log rank)= 0.09
0.0
0
1
years
2
Leukemia-free Survival
-Adjusted for Disease Status at Transplantation100
100
90
80
Probability, %
90
Matched BM vs. CB
RR 0.87, p=0.254
Matched PBPB vs. CB RR 0.89, p=0.177
80
BM matched, 41%
70
70
PBPC matched, 39%
CB, 33%
60
60
50
50
40
40
PBPC mismatched, 34%
30
30
BM mismatched, 34%
20
20
10
10
Not in remission at HCT, RR 2.40, p<0.001
0
0
0
12
24
Years
36
24
New protocols for cord blood transplant
 Graft facilitation
 Unmanipulated Double cord transplant
 Co infusion of :
 Ex vivo expanded cells
 Intra bone unit
 Third party Mesenchymal cells
 Conditioning
 non myeloablative vs myeloablative
 role of Fludarabine
sUCBT versus dUCBT for adults with AL
2 y LFS
P=0.05
45 ± 3%
dUCBT
38 ± 3%
sUCBT
months
sUCBT versus dUCBT for adults with AL
2 years Relapse incidence
P=0.06
sUCBT
26 ± 2%
18 ± 3% dUCBT
months
sUCBT versus dUCBT for adults with AL
100 day CI of Acute GVHD II-IV
P=0.004
dUCBT
36 ± 3%
sUCBT
25 ± 2%
days
Discussion
• Long-term hematopoiesis derived from one of
the 2 CBU transplanted in double CBT
• Lower relapse for double CBT compared to single
CBT in CR1-2 patients
• More grade II acute GVHD in double CBT
• These
findings
suggest
an
increased
alloreactivity and immune graft vs graft
interaction.
COMPARISON OF OUTCOMES AFTER HLAIDENTICAL SIBLING CORD BLOOD vs BONE
MARROW TRANSPLANTS
IN CHILDREN
International Bone Marrow Transplant Registry
and
Eurocord
V Rocha, J Wagner, K Sobosinski et al,
NEJM 342: 1846-1854, 2000
Prise de neutrophiles après greffes HLA identiques de SCO
comparées aux greffes de MO chez les enfants
100
MO (N = 2,018)
SCO (N = 106)
PROBABILITE, %
80
60
40
20
P = 0.0001
0
0
30
60
90
120
150
180
210
240
V Rocha, J Wagner, K Sobosinski et al, NEJM 342: 1846-1854, 2000
270
300
330
360
jours
Survie Globale après greffes HLA identiques de SCO
comparées aux greffes de MO chez les enfants selon les
diagnostics
100
PROBABILITE DE SURVIE, %
Non malignes, SCO (N = 52)
80
Non-malignes, MO (N = 789)
Malignes, MO (N = 1,263)
60
Malignes, SCO (N = 61)
40
20
0
0
1
2
ANNEES
3
V Rocha, J Wagner, K Sobosinski et al, NEJM 342: 1846-1854, 2000
4
5
Première observation de très grande importance pour
l’évolution des greffes de sang de cordon ombilical:
La GvH aigue grades II-IV et la GvH chronique
sont diminuées
dans les greffes de SCO en comparaison avec les greffes de
MO
Family cord blood banking: facts
• The first cord blood transplant was performed in 1988
in a child with Fanconi anemia with his HLA identical
sister. Currently he is doing well with a full
hematological and immune reconstitution.
• Since HLA identical siblings cord blood transplants have
been performed in children with hematologic
malignant and non malignant diseases.
• Compared to HLA identical bone marrow transplants
cord blood transplant results in delayed engraftment,
decreased acute and chronic GVH and same survival.
Related CBT- Nb of transplants and follow-up
median = 2002
50
50
48
44
45
40
36
38
30
38
34
35
30
29
41
39
29
31
596 cord blood transplants
– 156 transplant centers
– 38 countries worldwide
– 89% transplants in EBMT
centers.
32
25
25
22
20
Median FU = 48 months
(range 3-248 months)
15
8
10
5
1 1
3 4
8
5
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
0
Related CBT- Diagnosis
Histiocytosis, 2 Metabolic disease, Other, 3
15
SCID, 36
ALL; 140
Hemoglobin.;193
(Thalassemia =145,
Sickle Cell
Disease=48)
AML, 46
Aplastic Anemia;
92 (Fanconi
Anemia=36, Other
Inherited BMFS= 30,
Acquired BMFS= 26)
Sec AL, 1
MDS, 26
CML, 21
NHL, 9
Hodgkin disease,
2
Solid tumor, 10
Related CBT- CB graft characteristics
All but 29 CB donors were HLA identical
Characteristics
Median
N
Min – Max
%
N
7
0 – 162.4
408
TNC/kg at infusion, (107)
3.9
0.7 – 68
431
CD34+/kg at infusion, (105)
1.5
1 – 63
334
Storage time of CBU, in months
395
ABO compatibility
-compatible
-minor incompatibility
-major incompatibility
Sex matched
262
50
83
67%
12%
21%
292
50%
577
Related HLA id CBT- Neutrophil recovery
• 477/519* pts reached ANC≥0.5 x 109/l, median time= 22 days (4-105)
Non Malignant disease (259/301): 94±3%
Malignant disease (188/218): 90±2%
p=ns
*Outcomes analysis performed in pts receiving HLA id CBT and with available information.
Related HLA-id CBT
Neutrophil recovery according to TNC dose and
CD34+ dose
High vs. Low TNC dose
High vs. Low CD34+ dose
CD34≥1.4x105/kg (129/139): 95±2%
TNC ≥3.9x107/kg (170/191): 92±2%
CD34<1.4x105/kg (124/146): 90±3%
TNC <3.9x107/kg (147/177): 88±3%
p=0.04
p=0.02
Related HLA-id CBT
Platelet recovery and acute graft-versus-host disease
318/519 patients reached a platelet count of ≥20 x 109/l.
Median time = 35 days (11-253 days)
Acute GVHD
CI aGVHD II-IV= 12±3%
Grade 3,
15 2,
Grade
52
Grade 1,
85
Grade 4, 4
None, 339
Related HLA-id CBT
Chronic graft-versus-host disease
CI cGVHD at 4 years= 13±2%
46/451 patients at risk:
• 38 limited
• 8 extensive
Related HLA-id CBT
OS according to diagnosis and year of CBT
Non Malignant disease vs Malignant disease
Non Malignant (259/301): 91±2%
Malignant (188/218): 56±4%
p=0.0001
Related HLA-id CBT for malignancies
Disease-free survival – Multivariate analysis
Factors
Year of transplant
≥2000
<2000
Patient’s gender
male
female
Disease status
high risk
low-interm. risk
Infused TNC
≥4.1 x 107/kg
<4.1 x 107/kg
HR
95% CI
P value Favorable factor
0.50
1.00
0.32 – 0.79
0.003
Transplant year ≥2000
1.68
1.00
1.05 – 2.70
0.03
Female gender
1.89
1.00
1.12 – 3.20
0.02
Low-interm. risk disease
0.55
1.00
0.34 – 0.89
0.02
Higher infused TNC
Factors included in the multivariate analysis model were year of transplant (<2000 vs. ≥2000), gender (F vs. M),
disease status (low-intermediate vs. high risk), infused TNC (<4.1 vs. ≥4.1 x107/kg) and use of MTX (no vs. yes).
Related HLA-id CBT for malignancies
Relapse in Acute Leukemia patients according to
remission status and use of TBI in MAC
1.0
0.8
0.6
No TBI (37/71): 55% ± 8%
TBI (28/72): 35% ± 6%
0.2
0.2
First CR (10/31): 33% ± 9%
TBI vs. no TBI: HR 0.52 (95%CI 0.290.94), p=0.03
0.4
0.4
Second CR (23/51): 46% ± 7%
≥Third CR (5/13): 39% ± 14%
Cumulative incidence of relapse
0.8
0.6
Refractory (9/14): 64% ± 14%
0
2
4
6
Years
8
10
p=0.03
0.0
p=0.04
0.0
Cumulative incidence of relapse
1.0
CR vs. No CR: HR 0.40 (95%CI
0.17-0.96), p=0.04
0
2
4
6
Years
8
10
Related HLA-id CBT for malignancies
Conclusions 1
• 3 main factors influencing outcomes:
– Cell dose
– Use of MTX
– Disease risk status
• Improvement of survival over time
– Decreasing use of MTX
– Better patient selection
• Increasing proportion of first and second CR AL patients
Related HLA-id CBT for malignancies
Conclusions 2
• Low incidences of NRM, acute and chronic GVHD
• Relatively high relapse incidence
– All HLA-identical related CB donors, less graft-versustumor effect
• Overall good survival after HLA-identical RCBT
support banking and use of HLA-identical sibling
CB, particularly in families from ethnic minorities.
Directed family cord blood banking
Advantages
• HLA identical sibling CBT give better results than
unrelated HLA mismatched CBT
• The sibling donor can give bone marrow or lymphocytes
later in case of relapse or rejection
• CB can be collected and cryopreserved in all siblings for
future matched or mismatched transplants when
indication is not immediate
• Patients affected with genetic diseases can have their own
cord blood collected and used for gene therapy ex
hemoglobinopathies.
Directed family cord blood banking
Disadvantages
• Use limited to children and only 25% are HLA identical
• Resource underutilized because of lack of organization
and funding
• Indication, Collection and Storage dependent on local
physician and facilities
• Most patients are located in developing countries
• Competition between the public and the private sector
Type of directed cord blood banks
• Family cord blood banking from healthy siblings of
patients who are candidates for allogeneic hematopoietic
stem cell transplant: most frequent indications are
hemoglobinopathies, leukemia VALIDATED
• Family cord blood banking from healthy siblings of
patients who are candidate for cell therapy for non
hematological diseases RESEARCH diabetis, cerebral palsy
• Family cord blood banking from healthy infants without
any known familial pathology. No indication of autologous
transplant for hematological diseases except in the case of
gene therapy. Indications for non hematological diseases
are investigated in the frame of RESEARCH PROTOCOLS
The Eurocord Office, Hôpital Saint-Louis, Paris