Hematopoietic Reconstitution in A Patien

Update on Cord Blood Transplants
Vanderson Rocha, MD, PhD
Scientific Director of Eurocord

Chair of Cord Blood Subcommittee of EBMT
Agence de Biomedecine and Saint Louis Hospital,
Paris, France
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

Twenty years later
Unrelated CBT- Non Malignant
Disorders
Clinical Results in Children

Clinical Results of Unrelated CBT in Children-
Non Malignant Disease n=352
n Median Outcomes Favourable Risk Ref
FU (m/y) Factors
Hurler Syndrome 93 29 m DFS: 70% Interval Dx-Tx >4.6 m BBMT 2009

Use of Bu/Cy
Hemoglobinopathy 30m Cell dose>5x107/Kg BBMT 2011

Thalassemia 35 DFS: 21%
SCD 16 DFS: 50%
Congenital Bone 44 32 m OS: 61% Cell dose>6.1x107/Kg Haemat.
2010
Marrow Failure Syn.
(excl FA)
Aplastic Anemia 71 35 m OS: 38% Cell dose>3.9x107/Kg BBMT 2010
Fanconi Anemia 93 22 m OS: 40% Cell dose>4.9x107/Kg BBMT 2007

Use of Fludarabine
Neg CMV serology
HLA
Unrelated CBT in Children- Non Malignant Disease
3- year Overall Survival for 3- year Overall Survival for

patients with Severe Aplastic patients with Fanconi
Anemia by cell dose (n=71) Anemia by cell dose (n=93)
Unrelated cord blood transplants in non
malignant diseases
• Cell dose is the most important factor a minimum

of 2x105 CD34+ cells/kg are necessary for
engraftment
• HLA matching is also important 0 to 1 HLA

matched donors with high cells counts must be
selected
• Indications and transplant protocols need

international cooperation
Unrelated CBT- Malignant Disorders
Clinical Results in Children

Malignant Disorders n=1122
FU (m/y) Factors
AML 390 24 m DFS: 46% Favorable karyotype ASH2011
Cunha R ,
CR1: 63% Disease Status Michel G et
CR2: 43% Cell dose>4.9x107/Kg al
Adv: 22%
MDS 70 39 m DFS: 39% Monosomy 7 Leukemia
2010
JMML 110 44 m DFS: 43% No Monosomy 7 ASH 2010

#533
Age<1y
HLA 0/1 difference
ALL 552 22 m DFS: 48% Disease Status ASH 2010
#532
CR1: 54%
CR2: 42%
Adv: 7%
Impact of 170 46 m DFS: Undetectable MRD Manuscript
in
Minimal MRD-: 54% Disease Status preparation
residual MRD+:29%
disease in ALL
2 years Leukemia-Free Survival
All patients (n=390)
Probability of Leukemia Free Survival
By disease status
at transplant (n=390)
Probability of Leukemia Free Survival

CR1: 63+4 %
46+3 % CR2: 43+4 %
Advanced: 22+5 %
p<0.001
Months
Month
s
Malignant Disorders n=1122
FU (m/y) Factors
AML 390 24 m DFS: 46% Favorable karyotype EHA 2011
# 1044
CR1: 63% Disease Status
CR2: 43% Cell dose>4.9x107/Kg
Adv: 22%
MDS 70 39 m DFS: 39% Monosomy 7 Leukemia
2010
JMML 110 44 m DFS: 47% No Monosomy 7 ASH 2010

#533
Age<1y
HLA 0/1 difference
ALL 552 22 m DFS: 48% Disease Status ASH 2010
#532
CR1: 54%
CR2: 42%
Adv: 7%
Impact of 170 46 m DFS: Undetectable MRD Manuscript
in
Minimal MRD-: 54% Disease Status preparation
residual MRD+:29%
disease in ALL
ALL DFS n=552
2-y LFS according to disease status at UCBT
CR1: 54±4%, n= 188
CR2: 42±4%, n= 254
Advanced: 7±2%, n=110 p=<0.0001

Minimal Residual Disease in childhood ALL,
(n=170)
Ruggeri A, ASH 2010
4-y LFS according to MRD assessment before UCBT
MRD-: 54±5%, n=96
MRD+: 29±5%, n=74
p=0.006
Clinical Results in Adults
Unrelated Cord Blood transplant

Clinical Results of Unrelated CBT in Adults (n=1052)

FU (m/y) Factors
Lymphoid 104 18 m DFS: 41% Chemosensitive disease JCO, 2009

malignancies Low-dose TBI
Cell dose>2x107/Kg
108 25 m DFS: 30% low-risk disease Leukemia,
2010
MDS
ALL 236 24 m DFS: 30% Disease Status Manuscript
in
preparation
Acute leukemia- 14 m DFS: KIR-ligand incompatibility Leukemia

2009
KIR 218 KIR-MM: HLA 0/1 mismatch
55%
KIR-M: 31%
Acute leukemia- 155 18 m DFS: 51% Disease Status Manuscript
in
RIC HLA 0/1 mismatch preparation
AML 604 14 m DFS: Disease Status Ruggeri, A

et al,
CR1: 45% #ASH 2011
CR2: 41%
Adv: 16%
UCBT for AML
2 y LFS according to disease status
CR1 (n=229): 45±4%
p=<0.001
CR2 and CR3 (n=228): 41±4%
Advanced (n=147): 16±7%
Ruggeri, A et al,
#1040 EHA 2011
Comparative Studies of cord blood
transplant with other stem cell
sources
Comparative study with other stem cell source in Children
n Median Results CBT compared Ref

FU with other sources
(m/y) (multivariate models)
Unrelated CBT vs UCB: 99 19 m Delayed engraftment Blood 2001
unrelated BMT for acute UBM: 442 32 m Decrease A and cGVHD
leukemia T-UBM:180 30 m Comparable LFS
Unrelated CBT versus UCB: 74 58 m Higher aGVHD Manuscript

in
haplo Related MMRD: 175 83 m Faster B cell recovery preparation
Transplant for SCID Comparable OS
Unrelated CBT versus Unr CB: 116 47 m OS of HLA matched UCB Manuscript
in
other SC source for idSIB BM: 37 62 m comparable to HLA preparation
Hurler Syndrome Unr BM: 105 80 m identical sibling
HLA 5/6 comparable to
10/10 HLA MUD
Comparison of outcomes of haploidentical related stem cell
and unrelated cord blood transplants in children with severe
T-cell deficiencies
5-year Overall Survival
62 ± 4% Haplo n=175
57 ± 6% UCB n=74
P (Cox): 0.61
years
Fernandes J et al submitted
Comparative study with other stem cell source in Children

FU with other sources
(m/y) (multivariate models)
Unrelated CBT vs UCB: 99 19 m Delayed engraftment Blood 2001
unrelated BMT for acute UBM: 442 32 m Decrease A and cGVHD
leukemia T-UBM 30 m Comparable LFS
Unrelated CBT versus UCB: 74 58 m Higher aGVHD Manuscript

in
haplo Related MMRD: 175 83 m Faster B cell recovery preparation
Transplant for SCID Comparable OS
Unrelated CBT versus Unr CB: 116 47 m OS of HLA matched UCB Manuscript
in
other SC source for idSIB BM: 37 62 m comparable to HLA preparation
Hurler Syndrome Unr BM: 105 80 m identical sibling
HLA 5/6 comparable to
10/10 HLA MUD
Children with Hurler disease
Disease Free Survival by type of donor and HLA
1,0
HLA identical sibling 81±6% or HLA 6/6 unrelated CB 81±8%

,9
,8
HLA matched unrelated donor 10/10 66±7% or CB 5/6 68±6 %

,7
,6
Unrelated CB 4/6 57±9% ( if high CD34 cell dose EFS=73±13%)

,5
,4
HLA matched low resolution or mismatched (antigen or allelic level)
,3 (incl. T cell depleted) 41±7%
,2
,1 P=0.004
,0
0 10 20 30 40 50 60
Boelens J and Rocha V on behalf of Eurocord, CIBMTR, Minneapolis and Duke University
Comparative study with other stem cell source in Adults
FU (m/y) with other sources
(multivariate models)
HLA (6/6) UBM UBM:584 27 m Delayed myeloid NEJM 2004

versus Single UCB:98 recovery
UCB Decreased a and cGVHD
for acute Comparable OS and DFS
leukemia
Compared to 8/8 UBM Lancet Onc
2010
HLA (7/8 and UBM: 364 26 m Delayed myeloid
8/8) UBM, PBSC UPBSC: 768 24 m recovery
and Single UCB UCB: 148 29 m Increased NRM but
for acute comparable OS and DFS
leukemia
RIC -(8/8) PBSC: 284 32 m Delayed myeloid Manuscript in
preparation
Unrelated PBSC UCB: 75 24 m recovery
versus RIC-UCBT Decreased cGVHD
for lymphoid Comparable OS and DFS
malignancies
Impact of Stem Cell Source in Adults with
Acute Leukemia, n=1280
Leukemia-free Survival
100
-Adjusted for Disease Status at Transplantation- 100
90 Matched BM vs. CB RR 0.87, p=0.254 90

Matched PBPB vs. CB RR 0.89, p=0.177
80 80
BM matched, 41%
70 PBPC matched, 39% 70
Probability, %
CB, 33%
60 60
50 50
40 40
PBPC mismatched, 34%
30 30
BM mismatched, 34%
20 20
10 Not in remission at HCT, RR 2.40, p<0.001 10
0 0
0 12 24 36 24
Years
Eapen M, Rocha V, Lancet Onc 2010
Comparative study with other stem cell source in Adults
FU (m/y) with other sources
(multivariate models)
HLA (6/6) UBM UBM:584 27 m Delayed myeloid NEJM 2004

versus Single UCB:98 recovery
UCB Decreased a and cGVHD
for acute Comparable OS and DFS
leukemia
Compared to 8/8 UBM Lancet Onc
2010
HLA (7/8 and UBM: 364 26 m Delayed myeloid
8/8) UBM, PBSC UPBSC: 768 24 m recovery
and Single UCB UCB: 148 29 m Increased NRM but
for acute comparable OS and DFS
leukemia
RIC -(8/8) PBSC: 284 32 m Delayed myeloid Manuscript in
preparation
Unrelated PBSC UCB: 75 24 m recovery
versus RIC-UCBT Decreased cGVHD
for lymphoid Comparable OS and DFS
malignancies
RIC-UCBT vs. RIC-MUD Transplantation
for Lymphoid Malignancies
PROGRESSION-FREE SURVIVAL
100
80 p = ns
Probability (%)
60
PBSC MUD (n=284)
40 ±2 at 2y
41%±
20 UCBT (n=75)
±6 at 2 y
38%±
0
Months 0 24 48 72 96
MULTIVARIATE ANALYSIS
HR CI 95% p
Use of CB 1.33 0.88-1.99 0.18
Non-indolent vs. indolent 1.69 1.21-2.35 0.002
Refractory disease 2.02 1.53-2.67 <0.0001
Comparison between cord blood and
other sources of stem cells
• Same survival and disease free survival
• Engraftment is delayed
• Less acute and chronic GVHD

Alternative donor transplantation: results of
parallel phase II trials using HLA-
HLA-mismatched
related bone marrow or unrelated umbilical
cord blood grafts.
Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, Devine SM,
Wingard JR, Aljitawi OS, Cutler CS, Jagasia MH, Ballen KK, Eapen M,
O'Donnell PV.
Blood. 2011
Demographic and Disease Characteristics
Cord (0604) Haplo (0603)
N=50 N=50
Median age (range) 58 (16-69) 45 (7-70)
Performance status > 90% 40 (80%) 38 (76%)
Disease
AML (CR1/CR>1) 29 (18/11) 22 (10/12)
ALL (CR1/CR>1) 6 (4/2) 6 (3/3)
Biphenotypic/undiff leukemia 1 3
Burkitt lymphoma 1 0
Hodgkin lymphoma (CR/PR) 5 (2/3) 7 (3/4)
Large cell lymphoma (CR/PR) 3 (2/1) 8 (3/5)
Mantle cell lymphoma (CR/PR) 0 3 (1/2)
Marginal zone or follicular NHL 5 1
Prior autologous Transplant 6 (12%) 11 (22%)
RIC--Treatment Schemas
RIC
Cord
Haplo
*May substitute other CNI

Relapse and Non-
Non-Relapse Mortality
Cord (0604) Haplo (0603)
Overall and Disease-
Disease-free Survival
Cord (0604) Haplo (0603)
95% CI, 44%
95% CI, 38-67%

73% ± 8 at 1 yr 2-year Overall Survival
62% ±10
Overall Survival
CR1 +CR2 (n=30)

Haplo BMT
p= 0.014 in 42 AML
19% ±12 Rome Transplant Network
advanced n=12
years from BMT
CR1+CR2 (n=77)
2-year Overall Survival 63±8%
Overall Survival
CBT
in 98 AML 8±7%
EUROCORD
Advanced (n=21)
months
New developments
UCBT Haplo
Double cord
Unmanipulated primed
Engraftment Ex vivo expansion
graft: BM +PBSC
Intrabone
NIMA Mother
Choice of the donor KIR NIMA
HLA-C KIR
NK NK
Immune
CTL CTL
reconstitution
Tregs T regs
T regs Tregs
GVH prevention
MSC MSC
NK
Prevention of relapse NK
DLI
Improving Outcomes after CBT
Current problems: engraftment and

immune reconstitution
Experimental and clinical approaches to improve engraftment
after UCB transplantation
(V Rocha and H Broxmeyer, BBMT 2010)
• Increase number of cells at cord blood collection
Banking cord blood units with greater volume and high number of CD34+ cells
Per fusing the placental vessels after draining the blood from the cord
• Enhance homing of cord blood cells
Inhibiting the enzymatic activity of CD26/Dipeptidylpeptidase IV (DPPIV)
In vivo direct injection of cord blood cells into the iliac crest (Phase II clinical trials)
• In vitro and in vivo expansion of cord blood cells
Using of SDF-1/CXCL12 associated to Diprotin A and/or other cytokines
Using Notch-ligand Delta 1 (Phase II clinical trials)
Using Copper chelator tetraethylenepentamine (TEPA) (Phase II clinical trials)
• Identification of modifiable prognostic factors for engraftment
Choosing the “best” cord blood unit based on cell dose, HLA, diagnosis, screening for
antibodies against HLA, quality of cord blood units
Modifying the conditioning regimen and GVHD prophylaxis
• Increase number of cells at infusion
Using double cord blood transplantation (on going prospective and observational studies)
Using third party mobilized T cell depleted haploidentical cells (Phase II trials)
• Decreasing toxicity and shorten time of aplasia
Using reduced conditioning regimen (on going prospective and observational studies)
• Co-infusion of cord blood cells with accessory cells
Using multipotent mesenchymal stromal cells (Phase I/ II trials)
Criteria of donor choice
Recommendations 2010
1. First look at the number of cells in MAC, RIC , single and double CBT
: collected >2.5x107 NC/kg et/ou>
et/ou>1.5x105 CD34+/kg
Infused >2.0x107 NC/kg
2. Search for antibodies against HLA
2. Second look at HLA

0-1 mm better than 2 avoid 3-4 mm
Prefer class I mismatches than class II (does not matter in
advanced phase of disease
disease?)
?)
If no choice increase the number of cells
It seems that in double CBT number of HLA disparities and ABO
compatibility is also important
3. Then adapt to graft indication

Malignant diseases:
diseases: cell dose is the best prognostic factor
because HLA differences reduce relapse (GVL)
Non malignant diseases
diseases:: increase cell dose (>4.0x107 NC/kg and
>2.0x105 CD34/kg ) and find the best HLA match
Criteria of CB unit choice
• Which is the best cell count marker : NC? CD34? CFU-GM?
• Is viability of NC or CD34 associated with engraftment?
• Is HLA allele typing important in CBT?
• Is HLA-C important in the selection of the cord blood unit?
• Is NIMA important?
• Double and RIC: Cell dose and HLA? Other?
• Are there other factors related to the CB unit that can improve
outcomes?
KIR ?
Years of Cord Blood Unit storage ?
ABO compatibility ?
Donor gender ?
Bank effect? and standards?
outcomes?
KIR ?
ABO compatibility ?
Donor gender ?
Lancet Oncology
Study Objectives
This analysis focused on two questions:
What is the impact on outcomes if matching

at HLA-A, -B, -C, -DRB1 is considered?
What is the impact on outcomes if matching

at the HLA-C locus is considered in addition
to matching at HLA-A, -B, –DRB1?
Study Population
N = 803 donor-recipient pairs

Leukemia or MDS
85% had acute leukemia
65% were aged <16 years
Disease status at transplantation
35% - 1st CR, CP
40% - 2nd CR, CP, AP
25% - active disease
Study Population
All received single CB unit

Myeloablative conditioning regimen
55% - TBI containing regimens
75% - anti-thymocyte globulin
All most all patients received cyclosporine
containing GVHD prophylaxis
Median infused TNC 3.8 x 107/kg
Median follow-up, 2 years
Statistical Analysis
Donor-recipient HLA match was examined in
five separate models:
Model 1: HLA-match at A, B, C, DRB1 (8/8
vs. 7/8 vs. 6/8 vs. 5/8 vs. 4/8)
Model 2: HLA-C match vs. HLA-C MM in
donor-recipient pairs either matched, 1-
locus MM, 2-loci MM or ≥3-loci MM at HLA-A,
-B or –DRB1
Models 3, 4 ,5: three additional models,
similar to model 2 but considered the
individual effect of HLA-A, -B or –DRB1
rather than HLA-C
Donor--recipient HLA match
Donor
Matching at 8-loci
8/8 HLA match = 69 (9%)
7/8 HLA match = 147 (18%)
6/8 HLA match = 259 (32%)
5/8 HLA match = 253 (32%)
4/8 HLA match = 75 (9%)
HLA typing was performed using molecular
techniques with a minimum of antigen-split
level resolution for HLA-A, -B, -C
Allele-level resolution for HLA-DRB1
Donor--recipient HLA match
Donor
65% of donor-recipient pairs were

mismatched at HLA-C
75% were associated with a mismatch at
HLA-B
Isolated mismatches uncommon:
3% each at HLA-B and -C
7% each at HLA-A and -DRB1
Among the remaining 15%:
Mismatch at HLA-A + B was the most
common
Objective I
What is the impact on outcomes if

matching at HLA-A, -B, -C, -DRB1 is
considered?
Transplant--related Mortality
Transplant
100 100
— 8/8 HLA match
— 7/8 HLA match
80 — 6/8 HLA match 80
— 5/8 HLA match
— 4/8 HLA match
Incidence, %
60 36% 60
33%
40 40
31%
20 20
19%
9%
0 0
0 1 2 3
Years
Relapse
100 100
— 8/8 HLA match

80 — 7/8 HLA match 80
— 6/8 HLA match
— 5/8 HLA match
Incidence, %
— 4/8 HLA match

60 60
44%
40 31% 40
33%
20 26% 20
26%
0 0
0 1 2 3
Years
Overall Survival
100 100
— 8/8 HLA match
— 7/8 HLA match
80 — 6/8 HLA match 80
— 5/8 HLA match
— 4/8 HLA match
Probability, %
60 60
51%
40 40
40% 37%
49%
20 20
40%
0 0
0 1 2 3
Years
Objective II
The impact of mismatching at specific

HLA-loci was examined:
HLA-C match vs. HLA-C mismatch in
donor-recipient pairs either matched or
1, 2 or ≥3-loci mismatched at HLA-A, -B
or –DRB1
Matching at HLA-A, -B, or –DRB1 rather
than HLA-C was examined in a similar
manner
Treatment--related Mortality
Treatment
100 100
— 6/6 + C matched
80 — 6/6 + C mismatched 80
— 5/6 + C matched
— 5/6 + C mismatched
Incidence, %
60 60
31%
40 40
26%
20 20
19%
9%
0 0
0 1 2 3
Years
Overall Survival
100 100
— 6/6 + C matched
— 6/6 + C mismatched
54%
80 — 5/6 + C matched 80
— 5/6 + C mismatched 51%
Probability, %
60 60
51%
40 40
37%
20 20
0 0
0 1 2 3
Years
Other Factors Associated with
Survival
Higher mortality
Patients older than 16 years
CMV seropositivity
Disease status
Not in remission at transplantation
Disease status is the only one potentially

modifiable by the physician by performing
transplantation early in the course of disease
Summary
Higher TRM after transplants mismatched
at any two or more loci
at HLA-C
Matched at HLA A, B, DRB1 (6/6)
Mismatched at a single A, B or DRB1 locus
(5/6)
at HLA DRB1
Mismatched at a single A, B, or C locus
Conclusion
Altering current selection strategies for cord
blood units may ameliorate some of the excess
TRM
Consideration of matching at HLA-C in addition
to HLA-A, -B and –DRB1 is warranted in some
situations
Consulting an HLA expert at the time of initial
search can help develop a search strategy
based on the patient’s HLA-type that will
maximize the likelihood of identifying a unit
matched at HLA-C
outcomes?
KIR ?
ABO compatibility ?
Donor gender ?
Impact of Matching at NIMA on
Outcomes after 5/6 or 4/6
Mismatched UCBT for Malignant
Hematological Diseases.
A matched pair analysis on behalf of

Eurocord, Netcord, NMDP and
CIBMTR
V Rocha, D Purtill, M-J Zhang, S Spellman,

A Ruggeri, V Prasad, C Navarette,
G Koegler, E Beaudoux, L Baxter-Lowe,
MM Horowitz, JJ van Rood, J Kurtzberg,
E Gluckman, M Eapen
Background
It is speculated that in utero exposure to NIMA
antigens induces partial tolerance to NIMA in a
significant proportion of individuals
• In kidney and Haplo HSC transplantaion
recipients grafts donated by the mother have
better outcomes
• Haploidentical bone marrow transplantation:

less GVHD and less TRM in group mismatched
for NIMA (approx. 50% of cases) rather than
NIPA haplotype (van Rood et al. Blood 2002)
• Unrelated Cord Blood Transplantation (7% of

NIMA matched) better neutrophil recovery,
trend of lower relapse (marginal effect only in
AML) , decreased non-relapse mortality after
NIMA-matched UCBT (van Rood et al; PNAS 2009)
NIMA matched in unrelated cord blood
transplantation
Mother of cord
IMA NIMA
A 24 A 32
Cord Patient
IMA IPA Haplotype 1 Haplotype 2

A 24 A 2 A 24 A 32
NIMA matched in unrelated cord blood
transplantation
Mother of cord
IMA NIMA
A 24 A 32
Cord Patient
IMA IPA Haplotype 1 Haplotype 2

A 24 A2 A 24 A 32
Objectives and selection criteria
To analyze the effect of NIMA-matching

on outcomes after UCBT
Donor maternal typing was available

for 508 donor-recipient pairs
All transplants were 5/6 or 4/6 HLA-

matched
Study Population
Donor-recipient pairs
N = 52 NIMA matched (10%)
N = 456 NIMA mismatched
Due to relatively low frequency of NIMA-

matched transplants, a matched-pair
analysis was performed
Variables for matching were determined

by multivariate analysis for non-relapse
mortality
Methodology
Cases/controls were matched on
Age
HLA-match
Disease status
Intensity of conditioning regimen
Additionally, cases were matched on

Disease
Infused total nucleated cell dose/kg
Study Population
48 NIMA matched recipients were

matched to 116 NIMA mismatched
recipients
Four NIMA matched recipients were

excluded
Unable to identify appropriate
controls
Characteristics of Matched Pairs
74% were aged ≤ 16 years
52% were male
Disease
88% had acute leukemia; ≈ half had
AML
9% had MDS; 2% NHL and 1% CML
Disease status
25% early; 50% interm.; 25% advanced
80% received myeloablative regimens
85% received CsA; 15% tacrolimus
Results
- Multivariate Analysis -
2.60
2.40
2.20
Hazard Ratio
2.00
1.80
1.74
1.60 1.63
1.59
1.40
1.20 1.18
1.00
0.94 0.85
0.80 0.79
0.60 0.55
0.44
0.40
0.20
0.00
ANC Acute Chronic

recovery GVHD GVHD Me11_10.ppt
Non--Relapse Mortality
Non
100 100
80 80
Incidence, %
60 60
NIMA mismatched HCT, 32%

40 40
20 20
NIMA matched HCT, 18%
0 0
0 1 2 3 4 5
Years
Me11_13.ppt
Results
2.00
1.80
1.60 P = 0.47
Hazard Ratio
1.40
1.43
1.20 P = 0.05
1.01
1.00
0.80 0.82
0.60
0.48
0.47
0.40
0.23
0.20
0.00
NRM Relapse
Relapse
100 100
80 80
Incidence, %
60 60
40 NIMA mismatched HCT, 33% 40

20 20
0 0
0 1 2 3 4 5
Years
Me11_14.ppt
Results
2.00
1.80
1.60 P = 0.47
Hazard Ratio
1.40
1.43
1.20 P = 0.05
1.01
1.00
0.80 0.82
0.60
0.48
0.47
0.40
0.23
0.20
0.00
NRM Relapse
Overall Survival
100 100
80 80
Probability, %

60 60
40 40
NIMA mismatched HCT, 38%
20 20
0 0
0 1 2 3 4 5
Years
Leukemia--free Survival
Leukemia
100 100
80 80
Probability, %
60 NIMA matched HCT, 52% 60
40 40
NIMA-mismatched HCT, 35%

20 20
0 0
0 1 2 3 4 5
Years
Me11_11.ppt
Results
2.00
1.80
1.60
Hazard Ratio
1.40
1.20 P = 0.06 P = 0.04

1.00 1.01
0.98
0.80
0.60 0.65
0.61
0.40 0.42
0.38
0.20
0.00
LFS OS
Me11_8.ppt
Conclusion
We confirmed the previous analysis of the impact of

NIMA matched on NRM, OS and DFS but not on
relapse or neutrophil recovery
The importance of other factors such as HLA disparity,

cell dose and transplantation of NIMA matched grafts
must be examined in a larger series of patients
Should we consider NIMA matching as a selection

criteria for CB grafts, considering the low frequency
of NIMA match (7% to 10%)?
In vivo direct injection of cord blood cells into the iliac crest
Unrelated Cord Blood Transplantation:
Comparison After Single Unit Cord Blood
Intrabone Injection and Double Unit Cord Blood
Transplantation In Patients with Hematological
Malignant Disorders. A Eurocord-EBMT Analysis
Vanderson Rocha, Myriam Labopin, Annalisa Ruggeri, Marina Podestà,
Dolores Caballero, Francesca Bonifazi, Rovira Montserrat, Andrea Gallamini, Gerard Socié,
E Nikiforakis, Mauricette Michalet, Erik Deconinck, Mohamad Mohty,
Andrea Bacigalupo, Eliane Gluckman, Francesco Frassoni
Intrabone single UCBT (ICBC) versus Double UCBT (dUCBT)
after MAC in patients with hematological malignancies
Cumulative Incidence of Neutrophil recovery (>=500)

90%
IBCB N=87
Median days: 23 90%
0.8
dUCBT N=149
0.6
Median days: 28
0.4
0.2
P=0.001
0.0
10 20 30 40 50 60
days
Intrabone single UCBT (ICBC) versus DoubleUCBT (dUCBT)
Cumulative Incidence of Platelets recovery (>=20.000)
IBCB N=87 81%

0.8
65%
0.6
dUCBT N=149
0.4
0.2
P<0.001
0.0
0 30 60 days 90 120 150 180

Cumulative Incidence of Acute GVHD (II-IV)
0.8
0.6
dUCBT N=149 47%

0.4
IBCB N=87
19%
0.2
P<0.001
0.0
0 10 20 30 40 50 60 70 80 90 100
days
Disease Free Survival
IBCB N=87 47%
dUCBT N=149
37%
months
Using double cord blood transplantation
Outcomes After Double Unit Unrelated Cord Blood
Transplantation (UCBT) Compared with Single UCBT in
Adults with Acute Leukemia in Remission.
An Eurocord and Acute Leukemia Working Party–EBMT
Collaboration Study [Abstract # 910]
Vanderson Rocha, Miriam Labopin, Mohamad Mothy, Guillermo Sanz, Bernard Rio, Sabine Furst,
Anne Sirvent, Gérard Socié, Reza Tabrizzi, Ybrahim Yakoub-Agha, Eric Deconinck, J.J
Cornelissen, William Arcese, Josep Maria Ribera, Emmanouel Nikiforakis, Mauricette Michallet,
Alessandro Crotta, Annalisa Ruggeri, Eliane Gluckman
Acute GVHD and relapse after single (n=378 ) versus double
UCBT (n=213 ) in adults with acute leukemia
100 day CI of Acute GVHD II-IV
0.8
0.6
dUCBT 39 ± 3%
0.4
sUCBT 21 ± 2%
2 years Relapse incidence in CR1
0.2
P<0.0001
0.0
0.8
30 60 90 120
0.6
0.4
sUCBT 25 ± 3%
0.2
dUCBT 15± 4%
P=0.03
0.0
0 6 12 18 24 30 36
months
2 years LFS after single (n=378) versus double UCBT (n=213)
in adults with acute leukemia
In First Complete Remission
In Second or Third Complete Remission
dUCBT 53±5%
sUCBT 39±4% dUCBT 35±5%
sUCBT 31±4%
months
In a multivariate analysis adjusted for differences and risk factors:
Double CBT was associated with improved LFS rates [p=0.04
HR=0.67 (0.45-0.97)]
months
Conclusion and questions
• HLA mismatched HSCT transplants are feasible, this
means that there is no shortage of donors
• Is MUD=CB=Haplo? All retrospective studies in children and
adults with acute leukemia showed that alternative sources
such as UBMT, UCBT or Haplo, can treat a number of patients
with some different outcomes but similar LFS
• Comparative registry-based studies are still necessary
• Collaborative Protocols should explore new methods
to improve results
The final choice of the SC source will depend on expertise

and policy of each center
Acknowledgments
EBMT , CIBMTR, Netcord
480 transplant centers in 49 countries

(data managers, nurses and physicians)
64 Cord Blood Banks

Hematopoietic Reconstitution in A Patien

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Hematopoietic Reconstitution in A Patien

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Update on Cord Blood Transplants

Vanderson Rocha, MD, PhD

Scientific Director of Eurocord

Gluckman E, Broxmeyer HE, Auerbach AD, Freidman HS,

N Engl J Med 1989;321:1174-1178

Clinical Results in Children

Hurler Syndrome 93 29 m DFS: 70% Interval Dx-Tx >4.6 m BBMT 2009

Hemoglobinopathy 30m Cell dose>5x107/Kg BBMT 2011

Fanconi Anemia 93 22 m OS: 40% Cell dose>4.9x107/Kg BBMT 2007

3- year Overall Survival for 3- year Overall Survival for

• Cell dose is the most important factor a minimum

• HLA matching is also important 0 to 1 HLA

• Indications and transplant protocols need

Clinical Results in Children

JMML 110 44 m DFS: 43% No Monosomy 7 ASH 2010

Probability of Leukemia Free Survival

46+3 % CR2: 43+4 %

JMML 110 44 m DFS: 47% No Monosomy 7 ASH 2010

CR1: 54±4%, n= 188

CR2: 42±4%, n= 254

Advanced: 7±2%, n=110 p=<0.0001

MRD-: 54±5%, n=96

MRD+: 29±5%, n=74

Unrelated Cord Blood transplant

n Median Outcomes Favourable Risk Ref

Lymphoid 104 18 m DFS: 41% Chemosensitive disease JCO, 2009

Acute leukemia- 14 m DFS: KIR-ligand incompatibility Leukemia

AML 604 14 m DFS: Disease Status Ruggeri, A

CR1 (n=229): 45±4%

CR2 and CR3 (n=228): 41±4%

Advanced (n=147): 16±7%

n Median Results CBT compared Ref

Unrelated CBT versus UCB: 74 58 m Higher aGVHD Manuscript

5-year Overall Survival

n Median Results CBT compared Ref

Unrelated CBT versus UCB: 74 58 m Higher aGVHD Manuscript

HLA identical sibling 81±6% or HLA 6/6 unrelated CB 81±8%

HLA matched unrelated donor 10/10 66±7% or CB 5/6 68±6 %

Unrelated CB 4/6 57±9% ( if high CD34 cell dose EFS=73±13%)

HLA (6/6) UBM UBM:584 27 m Delayed myeloid NEJM 2004

90 Matched BM vs. CB RR 0.87, p=0.254 90

10 Not in remission at HCT, RR 2.40, p<0.001 10

HLA (6/6) UBM UBM:584 27 m Delayed myeloid NEJM 2004

• Same survival and disease free survival

• Less acute and chronic GVHD

*May substitute other CNI

Cord (0604) Haplo (0603)

95% CI, 44%

95% CI, 38-67%

CR1 +CR2 (n=30)

years from BMT

2-year Overall Survival 63±8%

Current problems: engraftment and

2. Search for antibodies against HLA

2. Second look at HLA

3. Then adapt to graft indication

This analysis focused on two questions:

What is the impact on outcomes if matching

What is the impact on outcomes if matching

N = 803 donor-recipient pairs

All received single CB unit

65% of donor-recipient pairs were

What is the impact on outcomes if