donor and stem cell source selection...maladie auto-immune anamnèse ci relative / précaution avis...
TRANSCRIPT
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Donor and stem cell source selection
TRAINING COURSE 2013-2015
E. Baudoux
S. Servais
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Table of contents
• Introduction
• HPC sources and donor types
• HLA and matching
• Unrelated donor searches
• Donor choice and eligibility
• Search strategies (Sibling, UD, CB, no Haplo)
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Hematopoietic stem cell transplantation (HSCT) has become an
accepted therapy for many congenital or acquired disorders of the
hematopoietic system and has seen major changes in indications and
use of transplant techniques over the years.
EBMT Annual report, 2012
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09/10 preliminary data
Trend over 5 years : Donor type
Worldwide Network for Blood and Marrow TransplantationNGO in official relations with the World Health Organization
Unrelated stem cell sourcenot for publication
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AlloHSCT
Patient
Disease Transplant procedures
Graft
Disease control
Engraftment
Immune reconstitution
Conditioning regimen,GVHD prophylaxis
Age, performance status,comorbidity
Diagnosis, status, priortreatments
↓Transplant-related mortality (TRM)
↓GVHD
Challenges of allogeneic hematopoietic stem cell transplantation
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Table of contents
• Introduction
• HPC sources and donor types
• HLA and matching
• Unrelated donor searches
• Donor choice and eligibility
• Search strategies (Sibling, UD, CB, no Haplo)
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Hematopoietic Stem Cell (HPC)
sources
25/04/20127
ARMB-KAGB
PBSCBM CB
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DONOR TYPES
• Matched Sibling Donor
• Matched Unrelated Donor
• Unrelated CB Donor
• (Haploidentical Donor)
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DONOR
Adult versus CB unrelated donor
Adult volunteer Cord blood
Supply 10% loss/year unlimited
Delay 6 monthsImmediately
available
Risk to donor anesthesia (BM) none
NC dose OK OK for children
Engraftment Rapid Slow
Risk of GVHD High Low
HLA compatibility 8+ out of 8 4-5 out of 6
Probability 65% 100%
LIMITATION HLA CELLULARITY
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Number of stem cell donors and cord
blood units worldwide
Data from BMDW - Bone Marrow Donors Worldwide
22M stem cell donors 588,958 CBU’s
Any available
donor, if any
Best available
donor or CB
Best available
donor or CB
No alternative to
donors
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Donor/source of HPC
AutologousAllogeneic
Family Unrelated
BM (HPC, M) Patient Sibling Donor registries
PBSC (HPC, A) Patient Sibling Donor registries
Cord Blood (HPC, CB) Sibling CB Banks
Donor registries
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Table of contents
• Introduction
• HPC sources and donor types
• HLA and matching
• Unrelated donor searches
• Donor choice and eligibility
• Search strategies (Sibling, UD, CB, no Haplo)
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Human Leucocyte
Antigen
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• 12 genes on short arm of chromosome 6 :
– 3 HLA class 1 gene (A, B, C) : monomeric Ag (A, B, C)
– 9 HLA class 2 genes (DRA1, DRB1, DRB3, DRB4, DRB5, DQA1,
DQB1, DPA1, DPB1) : heterodimeric Ag (DRA1/DRB1,
DQA1/DQB1, DPA1/DPB1)
– DRB3, DRB4, DRB5 genes are mutually exclusive, are present
only on certain haplotypes, in relation with particular DR Ag
(DR52, DR53, DR51)
• Extreme polymorphism :
– Antigenic level : A, B, C, DR, DQ antigens
– Allelic level : A, B, C, DRA1, DRB1, DRB3, DRB4, DRB5, DQA1,
DQB1, DPA1, DPB1 genes.
Number of identified alleles increases constantly
DONOR
HLA system
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HLA alleles of importance for HSCTAssigned April 2012
• Range: 1023 genotypes
• Most frequent haplotype : A 01-B 08-DRB 0301
(6% of caucasians)
Locus N Alleles
A 1884
B 2490
C 1384
DRB1 1194
DQB1 165
sophie
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• Over 1023 genotypes
• Some alleles and some combinations of HLA alleles (haplotypes) are
rare and others frequent
Most frequent haplotype : A01-B08-DRB0301 (6% of caucasians)
• To make sure 2 siblings are genotypically identical, parental typing is
necessary to identify haplotypes
• If one of the parents is homozygous at Ag level, low resolution
typing does not allow verification of genotypic identity between
donor and recipient
DONORHLA typing
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• Level of incompatibility :
– Antigenic (2-digit) : A*02 vs A*03
– Allelic (4-digit) : A*02:01 vs A*02:02
• Direction of incompatibility :
– GVH direction
– Rejection direction
– Both directions (most frequent)
DONOR
HLA incompatibility
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• Degree of compatibility :
– 12/12 : A-B-C-DRB1-DQB1-DPB1 (not much used)
– 10/10 : A-B-C-DRB1-DQB1 (generally by high resolution typing)
– 8/8 : A-B-DRB1-DQB1 (not much used)
– 6/6 : A-B-DRB1 (generally by low resolution typing)
• Type of compatibility :
– Genotypic : donor and recipient have received same 2 haplotypes
from their parents (twins, siblings)
– Phenotypic : donor and recipient have inherited one haplotype but
not the other or are unrelated
DONORHLA compatibility
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Donor
A* 02:02
B* 44:01
C* 03:03
DRB1* 01:01
DQB1* 02:03
Rejection GVHD
Ag Allele Ag Allele
A 0 0 1 0
B 0 0 0 0
C 0 0 0 0
DRB1 0 1 0 1
DQB1 0 0 0 0
Total 0 0.5 1 0.5
9.5/10 8.5/10
A* 02:02
B* 35:01
C* 04:03
DRB1* 08:02
DQB1* 04:03
Patient
A* 02:02
B* 44:01
C* 03:03
DRB1* 01:02
DQB1* 02:03
A* 04:03
B* 35:01
C* 04:03
DRB1* 08:02
DQB1* 04:03
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A 1
B 15
DR 11
A 31
B 16
DR 9
Mother Father
A 2
B 44
DR 3
A 3
B 27
DR 15
PatientSibling 1
A 2
B 44
DR 3
A 3
B 27
DR 15
A 2
B 44
DR 3
Sibling 2
A 2
B 44
DR 3
A 3
B 27
DR 15
A 31
B 16
DR 9
DONORHLA compatibility : genotypic
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A 31
B 16
DR 9
A 31
B 16
DR 9
Mother Father
A 2
B 44
DR 3
A3
B 27
DR 15
PatientSibling 1
A 2
B 44
DR 3
A 31
B 16
DR 9
A 3
B 27
DR 15
A 31
B 16
DR 9
A 2
B 44
DR 3
A 31
B 16
DR 9
Sibling 2 Sibling 3
A 31
B 16
DR 9
A3
B 27
DR 15
DONORHLA compatibility : phenotypic
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DONORMinimal and ideal compatibility
DONOR TYPEMATCH LEVEL
REMARKIDEAL MINIMUM
Identical twin By definition genotypically identical
Brother/sister (sibling) or
other family donor6/6
5/6 IF one haplotype is
genotypically identical.
If not, see MUD
Unrelated (MUD) 10/10 8/10 allelic*
Cord blood 6/6 4/6 antigenic Allelic match DRB1?
Haploidentical1 haplotype identical
Other haplotype: any
(*) Minimum 8/10 allelic:
• 1 antigenic MM (9/10) • 1 allelic + 1 antigenic MM (8.5/10)
• 2 allelic MM (9/10) • 1antigenic + 1 antigenic DQB1 (8/10)
Sophie et eurocord
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Table of contents
• Introduction
• HPC sources and donor types
• HLA and matching
• Unrelated donor searches
• Donor choice and eligibility
• Search strategies (Sibling, UD, CB, no Haplo)
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• Simultaneous VUD and CB search : based on type of HSCT
(mini vs conventional) and criteria in document TB0201M02-
Eligibilité et choix donneur.
• BMDW (Bone Marrow Donor Worldwide) : all UD/CB listed by
HLA compatibility with patient.
• MDP-B (Marrow Donor Program-Belgium) : Syrenad IT
system and EMDIS network connecting with foreign
registries including NMDP-USA.
• Netcord : CBB network, global search with NMDP-USA.
Belgian hub is MDP-B.
• Confirmatory HLA typing (CT) in TC on each donor before
start of conditionning.
DONORSearch for unrelated donors
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MDPB-REGISTRY
2011
MDP-B Registry
(Syrenad)
Unrelated
donors
Belgian
Patients
5 Cord blood
banks
>16 000 CBUs
7 donor centers
>60 000 Donors
10 Transplant
centers
(national
patients)
EMDIS
65 INTERNATIONAL
REGISTRIES44 CB BANKS
>23 M DONORS >600 000 CBUS
Internet
Internet
Internet
Searching for
national donorsSearching for
International donors
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Table of contents
• Introduction
• HPC sources and donor types
• HLA and matching
• Unrelated donor searches
• Donor choice and eligibility
• Search strategies (Sibling, UD, CB, no Haplo)
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• Choice: donor selection among a potential donors, based
on:
– HLA
– Age, sex, CMV, ABO …
– Donor preferences
• Eligibility : donor acceptance, based on absence of
contra-indication (non-conformity):– Donor safety
– Patient safety
DONORDonor choice & eligibility
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• Donor non conformity with any eligibility criteria may
constitute:
– Absolute contraindication to cell donation: in this
case,UMN (Urgent Medical Need) is not possible
– Relative contraindication to cell donation: in this case,
UMN (Urgent Medical Need) is possible after decision
of transplant committee and eventual specialized
opinions
– Precaution: cell donation is acceptable, but measures
may be necessary during the process of
collection/transplantation
DONORDonor eligibility : non-conformity
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DONOR
Donor eligibility : donor safetyEligibilité
Critère Type Inéligibilité Avis avant UMN
Document référence
Remarques
Grossesse Anamnèse Test biologique
PBSC : CI absolue
Moelle : CI relative
Lympho : CI relative
-
Gyneco / anesthésiste
Gyneco
TB0202M02
TB0202M01
TH0202M03
Test grossesse systématique CI absolue pour don CSM
Splénomégalie Clinique
PBSC : CI absolue
Moelle : CI relative
Lympho : OK
-
A voir selon cause
-
TB0202M02
-
-
CI absolue pour don CSM
Maladie auto-immune
Anamnèse
PBSC : CI relative
Moelle : OK
Lympho : OK
A voir selon cause
-
-
TB0202M02
-
-
Risque de « Flare-up » (G-CSF)
CI absolue pour don CSM
Traitement anti-coagulant
Anamnèse
PBSC : CI relative
Moelle : CI relative
Lympho : CI relative
A voir selon cause
A voir selon cause
A voir selon cause
TB0202M02
-
-
Sevrage à envisager CI absolue pour don CSM
Maladie thrombotique, coronarienne ou vasculaire
Anamnèse ECG
PBSC : CI relative
Moelle : CI relative
Lympho : précaution
Cardio
Cardio / anesthésiste
A voir
TB0202M02
-
-
CI absolue pour don CSM
Nécessité de cathéter central
Clinique PBSC / Lympho :
précaution Nephro - CI absolue pour don CSM
Autre pathologie
Anamnèse Clinique Test biologique Examens
A voir A voir - A voir par senior transplantation et/ou comité de greffe
TB0201M02-Eligibilité & choix donneur.doc
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DONORDonor eligibility : patient safety
TB0201M02-Eligibilité & choix donneur.doc
Eligibilité Critère Type
Inéligibilité Avis avant UMN
Document référence
Remarques
Maladie génétique Anamnèse CI relative Avis spécialisé TB0202A01 CI absolue pour don CSM
Maladie auto-immune
Anamnèse CI relative / Précaution Avis spécialisé SN - CI absolue pour don CSM
Cancer Anamnèse CI relative Avis onco TB0202A01 CI absolue pour don CSM
Vaccin tué/recomb. Anamnèse CI relative temporaire Avis infectiologie SN TB0202A01
Vaccin vivant/atten. Anamnèse CI absolue temporaire Avis infectiologie TB0202A01
Vaccin variole Anamnèse CI absolue temporaire TB0202A01
SARS Anamnèse CI absolue temporaire Avis infectiologie TB0202A01
Virus West Nile Anamnèse CI relative temporaire Avis infectiologie TB0202A01
Malaria Anamnèse CI relative temporaire Avis infectiologie TB0202A01 TB0601A04
CI absolue pour don CSM
Maladie Chagas Anamnèse CI absolue permanente TB0202A01 TB0601A04
CI relative si 2 tests négatifs CI absolue pour don CSM
Leishmaniose Anamnèse CI absolue permanente TB0202A01 TB0601A04
CI relative si sérologie négative CI absolue pour don CSM
Babesiose Anamnèse CI absolue permanente TB0202A01 CI relative si sérologie négative CI absolue pour don CSM
vCJD Anamnèse CI relative permanente TB0202A01 CI absolue pour don CSM
Creutzfeldt-Jakob Anamnèse CI relative permanente Avis neuro / infectiologie
(& autres) TB0202A01 CI absolue pour don CSM
Xenogreffe Anamnèse CI relative permanente Avis infectiologie TB0202A01 CI absolue pour don CSM
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DONORDonor eligibility : patient safety
TB0201M02-Eligibilité & choix donneur.doc
Eligibilité Critère Type
Inéligibilité Avis avant UMN
Document référence
Remarques
Anamnèse CI relative temp/perm Avis infectiologie TB0202A01 CI absolue pour don CSM HIV
Test biologique CI absolue permanente TB0601A03 Confirmation PCR
Anamnèse CI relative temp/perm Avis infectiologie TB0202A01 CI absolue pour don CSM HTLV-I
Test biologique CI absolue permanente - Confirmation PCR
Anamnèse CI relative temp/perm Avis hépatologie SN TB0202A01 CI absolue pour don CSM HB
Test biologique CI relative permanente Avis hépatologie SN TB0601A03 CI absolue pour don CSM
Anamnèse CI relative temp/perm Avis hépatologie SN TB0202A01 CI absolue pour don CSM HC
Test biologique CI relative permanente Avis hépatologie SN TB0601A03 CI absolue pour don CSM
Anamnèse CI relative temp/perm Avis hépatologie SN TB0202A01 HA
IgM CI relative temporaire Avis hépatologie -
Syphillis Test biologique CI relative Avis infectiologie TB0202A01 TB0601A01
CI absolue pour don CSM
Anomalie hémogramme
Test biologique CI relative Moelle & bio - Exploration hémopathie CI absolue pour don CSM
Gammapathie monoclonale
Test biologique CI relative Moelle & bio - Exploration MM CI absolue pour don CSM
Etat ferriprive inexpliqué
Test biologique CI relative Gastro & colono - Exploration cancer digestif CI absolue pour don CSM
Anomalie hépatique
Test biologique CI relative HB-HC-EBV-HHV6-Adeno
Avis hépato -
Exploration hépatite virale (PCR) CI absolue pour don CSM
Autre pathologie
Anamnèse Clinique Test biologique Examens
A voir A voir - A voir par senior transplantation et/ou comité de greffe
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TB0201M02-Eligibilité & choix donneur.doc
CRITERES SECONDAIRES
Transfusion CMVSexeAge ABO
Choisir
Non transfusé
Choisir
CMV
Don = Rec
Choisir
Homme
(sauf haplo :
mère)
Choisir
Jeune
Choisir
ABO
compatible
Risque
GVHD ?
Risque
CMV
AGVHD
Risque
CGVHD
Risque
Engraftment
Survie
Risque
TRM (mineur)
PRCA (majeur)
Poids
Choisir
Poids
Don > Rec
Risque
Engraftment
Eviter
Transfusions
Eviter
CMV + → -
CMV - → +
Surtout haplo
CB ?
Eviter
Parité
F → H
Si :
HLA-id sib
UD 10/10
Eviter
Famille :
> 70 ans
UD :
selon registre
Eviter
ABO mineur
(si PBSC)
ABO majeur
Eviter
Poids
Don << Rec
KIR
Choisir
KIR
mismatch
sens GVH
(voir texte)
Risque
Rechute
(Myéloïde >)
Eviter
KIR
compatible
Si :
Haplo-identique
UD avec TCD ?
Anti-HLA
Choisir
Donneur
contre qui pas
d’anti-HLA
Risque
Engraftment
Eviter
Donneur
contre qui a
Ac anti-HLA
Surtout :
RIC/Mini
CB
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Donor age
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Donor age
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UD CBT in patients with malignant diseases
Days0 10 20 30 40 50 60
0.0
0.2
0.4
0.6
0.8
1.0
2,1-3,2: 72%+3
>5,2: 78%+3
3,2-5,2: 76%+3
p<.00001
<2,1: 63%+3
Neutrophils engraftment according to the class of NC infused x107/kg
(CI)
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Barker et al. Blood 2010
Neutrophil engraftment TRM DFS
UCB cell dose
↑ UCB cell dose ↑ engraftment / ↓ TRM / ↑ survival
Total nucleated cell dose (per kg recipient weight)
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↑ UCB cell dose ↑ engraftment / ↓ TRM / ↑ survival
Total nucleated cell dose (per kg recipient weight)
CD34+ cell dose (per kg recipient weight)
Progenitor cell dose (per kg recipient weight)
Pla
tele
tsen
graf
tmen
t
CD34 dose (x105/kg) CFU (x104/kg)
Page et al. BBMT 2011
TRM
UCB cell dose
Wagner et al. Blood 2002
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Impact of donor-recipient HLA-matching at HLA-A, -B, -C and –
DRB1 on outcomes after umbilical cord blood transplantation for
leukemia and myelodysplastic syndrome: a retrospective analysisEapen, Lancet Oncol. 2011
• MM HLA-C is an independent risk factor for transplant-related mortality when transplants are matched at HLA-A, -B, -DRB1 or mismatched at a single HLA-A, -B or -DRB1 locus
• MM HLA-DRB1 when transplants are mismatched at a single HLA-A, -B or –C locus is an independent risk factor for transplant-related mortality
• If a unit matched at HLA-A, -B, -C and –DRB1 is not available, selecting a unit matched at HLA-C is preferred; in particular avoiding a mismatch at HLA-C in the presence of a single mismatch at HLA-DRB1 significantly lowers mortality risks.
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The NIMA effect
(Non Inherited Maternal Antigen)Rocha et al, 2012
• Fetal exposure induces lasting tolerance to NIMA (better
outcome in renal Tx)
• HLA MM CBT with NIMA match show lower TRM (A) and
better OS (B)
• When HLA MM CBT, preferably NIMA match
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Impact of allele-level HLA matching on outcomes after
myeloablative single unit umbilical cord blood transplantation
for hematologic malignancy
Eapen et Al. Blood 2013
USA
(180,000 CBU inventory)
CaucasiansNon-
Caucasians
Full allele match UD CBU 33% 5-10%
1 allele MM 80% 33-45%
2 allele MM 98% 80-85
• Low or IR level match without HLA-C match selection of UD CBU not optimal
• If full allele match not available: 1-2 allele MM better
tolerated than 3+ alleleMM (10-15% differencein NRM)
Single MM HLA A, C, DRB1 NRM x 3
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Impact of allele-level HLA matching on outcomes after
myeloablative single unit umbilical cord blood transplantation
for hematologic malignancy 2
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Table of contents
• Introduction
• HPC sources and donor types
• HLA and matching
• Unrelated donor searches
• Donor choice and eligibility
• Search strategies (Sibling, UD, CB, no
Haplo)
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Finding a MUD
Search success rates and duration
Search success rates (>23 million
VUDs)
8/8 match: 40 – 60%
1 antigen mismatch: 60 – 90%
Median search duration: 22 d – 2.5 mo
Median time to transplant: 2 – 4 mo
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0 1 2 3
Años
1
0.8
0.6
0.4
0.2
0
Pro
ba
bilid
ad
de
do
na
nte
3 m
44%
6 m
57%
12 m 65%
70%
Alternative donor necessary
Alternative donor
preferable
Actuarial probability of finding a 7/8 or 8/8 MUD
in Spain (Memoria REDMO 2009)
Years
Pro
babili
ty t
o d
onate
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Alternative donor allogeneic transplantation:
criteria for choosing MUD vs. CBT vs. Haplo
V. Rocha, F. Locatelli. BMT 41, 207–214; 2008
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Strategy of alternative stem cell donor
High resolution HLA typing of the patient
Ruggeri A. et al. Best Practice @ Res. Clin. Hematol. 23:207-216, 2010
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1
2
also if PB
Similar OS
HOW TO SELECT THE OPTIMAL GRAFT SOURCE ?
MUD> Old MRD?
3
No consensus
Similar OS, late infectionsEarly CD4+ T-cell reconstitution
3 3
↑ CD34+
Avoid FM
Young
CMV-
ABO=
↑ CD3+
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Upcoming concerns for donor/CBU
selection
• Donor
– Consider age!
– CMV
– HLA antibodies in recipient
• CBU
– Seek HLA C match
– Seek max. 1-2 Allele MM
– Take into account NIMA effect for MM CB units
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Thanks
• Sophie Servais
• Yves Beguin
• Carlheinz Muller (ZKRD)