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Outcomes Using Single and Double Unit Cord Blood Transplant Grafts
1. Outcomes Using Single and Double Unit
Cord Blood Transplant Grafts
Vanderson Rocha, MD, PhD
Eurocord
Hôpital Saint Louis, Paris
2.
3. Overcoming the Cell Dose Limitation
If no single graft is big enough then …
HLA A & B: Ag level
HLA DRB1: Allele level
4/6
-8 -7 -6 -5 -4 -3 -2 -1 0
TBI
MMF
CSA
G-CSF
FLU
CY
FLU
CY
FLU
DUCBT
4. Use of Unrelated Stem Cell Sources
in the U.S. for 2006 - 2010
Age ≤ 16 yrs Age > 16 yrs
0
20
40
60
80
100
2006-2010 2006-2010
Bone Marrow (BM)
Peripheral Blood (PB)
Cord Blood - single
Cord Blood - multiple
Transplants,%
5. Eurocord Registry
General data base* overview
*Eurocord Registry status as off December, 31st, 2012
Eurocord registry database N or %
Cord blood units / European CB units % 12 066 / 58%
CBT cases (single% / double%) 9 883 (63% / 23%)
European CBT cases 65%
Countries / Centres / EBMT centres 51 / 577 / 297
Unrelated CBT cases 93%
Children CBT cases 54%
6. Eurocord Registry at ABM
Unrelated European CBT by recipient’s age and graft type
Children Adults
* Still collecting 2012 data
0
50
100
150
200
250
300
1990
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
Double CBT
Single CBT
*
0
50
100
150
200
250
300
350
400
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
Double CBT
Single CBT *
In children: 92% single CBT In adults: 47% double CBT
7. Should Transplantation of Two Cord
Blood Units be the Standard for
Adults?
Approximately 80 - 85% of cord blood
transplants in the U.S. and 50% in Europe,
infuse two units
Practice variation
Likely that some of these patients may have
had an adequately dosed single unit
Majority with TNC (sum of unit 1 & 2) in
excess of 3 x 107/kg
8. Should Transplantation of Two Cord
Blood Units be the Standard for
Adults?
Ideal study design
Randomized trial
Each patient has an adequately dosed single
unit
Randomized to receive one or two units
A similar trial in children / adolescents ( J
Wagner and J Kurtzberg)
None planned in adults – feasibility
9. Minnesota Studies
• Double UCBT promotes engraftment, achieving
rates comparable to single UCBT with adequate
cell doses: mechanism unknown
immune mediated or additive effect?
• Risk of grade 2-4 aGVHD is higher after double
UCBT (although no difference in risk of grade 3-4
aGVHD)
• Risk of cGVHD is similar
• Reduced risk of relapse is associated with
– Double UCBT
– Early disease status (CR1 & 2)
– No Benefit from aGVHD
10. Overall Survival
CR1 & CR2
Years
Probability
p = .16
0.0
0.2
0.4
0.6
0.8
1.0
0 1 2 3
II
I I I
I
I I II
I II
I
II
II I I I II I I II I I I III
Double
Single
72% (56-88%)
47% (51-75%)
13. Study Design
Used data reported to observational
registries
CIBMTR; N = 327
NYBC; N = 79
All single units contained
TNC ≥2.5 x 107/kg
Lower TNC limit for 1 unit CBTs: BMT CTN 0501
Almost all two UCB unit transplants
TNC ≥3 x 107/kg
≈10% of 1 unit TNC < 1.5 x 107/kg
14. Study Population
N = 303 recipients of double UCBT
N = 106 recipients of single UCBT
AML or ALL
Transplant period: 2002 – 2009
Several differences b/w two groups
Single UCB recipients were younger,
more likely to be in relapse, MAC
conditioning regimen, 6/6 or 5/6
HLA-matched to donor, lower TNC
and transplanted prior to 2005
23. SUMMARY
These data confirm
Infusing 2 UCB units overcomes the cell
dose barrier
Thereby making this treatment accessible
to a substantial number of adults
Survival after transplantation using a
single unit (adequate dose) is comparable
to that after two units
24. 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
25. Double versus Single UCBT in Adults with AL
by conditioning regimen
Selection criteria
• First single or double UCBT performed in transplant centers in
Europe
• Transplants performed from 2005-2011
• Adults ≥ 18 years old with AML or ALL in first or second CR
• Single CBU with adequate TNC at collection (>2.5x107/Kg)
• Two different analysis : Myeloablative or Reduced Intensity
Conditioning Regimen
MAC: 402 patients (241 sUCBT and 161 dUCBT)
RIC : 360 patients (229 dUCBT and 131 sUCBT)
26. Outcomes After Double UCBT Compared with
Single UCBT in Adults
with Acute Leukemia in Remission after
Myeloablative Conditioning Regimen
27. Selection Criteria
• Adult patients with ALL and AML, in CR1
•UCBT from 2005 to 2011 in EBMT centers
• Single and double UCBT
• Myeloablative conditioning regimen
239 patients were evaluable
28. Patients and disease characteristics, n=239
Patients Characteristics AL in CR1, n=239
Median Follow-up 24 (3-74) months
Median age at UCBT (years) 34 (18-63)
Diagnosis, n
AML
ALL
138
101
High risk cytogenetics
T(9;22), n
FLT3/ITD, n
56%
42
26
Interval diagnosis-UCBT 180 days
Single UCBT 156 (61%)
Double UCBT 83 (39%)
•There were no statistical differences between single and double UCBT for those
characteristics
29. Characteristics, n=239
• Pts were transplanted with sUCBT (n=156) or dUCBT
(n=83)
• Type of MAC was statistically associated with outcomes
therefore pts were analyzed in 3 different groups:
– Group 1: sUCBT with TBI-based+Cy (+Flu) (n=68) (performed in
42 transplant centers (TC)),
– Group 2: sUCBT with Bu+Flu+Thiotepa (n=88) (performed in 23
TC) and
– Group 3: dUCBT with Cy+TBI+Flu (n=83) (performed in 47 TC)
Group 1,
sUCBT- TBI
based+Cy
(+Flu)
28%Group 2,
sUCBT-
Bu+Flu+Thio
tepa
37%
Group 3,
dUCBT-
Cy+TBI+Flu
35%
30. Type of Graft and Conditioning Regimen, n=239
Graft Characteristics
Group 1, sUCBT
TBI-based+Cy
n=68
Group 2, sUCBT
Bu+Flu+Thio
n=88
Group 3, dUCBT
Cy+TBI+Flu n=83
HLA match*
6 and 5 out of 6 31% 30% 26%
4 out of 6 69% 70% 74%
Median TNC after
thawing (107
Kg)
2,9 (1,5- 8) 3 (1,2- 6) 3,7 (1,3- 6)
Median CD34+ cells
after thawing (105
Kg)
1,2 (0,3- 7) 1,6 (0,3- 15) 1,5 (0,2- 7)
ATG use before day 0 70% 90% 40%
*HLA A, B antigenic level - DRB1 allelic level
No statistical differences were found among the 3 groups for patients disease and transplant characteristics
(diagnosis, risk, gender, weight, CMV status, year of UCBT, time from diagnosis to UCBT, cytogenetic risk class, number of HLA disparities)
however patients in group 2 were older than in group 1 and 3 (median age 38 vs 33 vs 31 years) (p=0.03).
31. 0 10 20 30 40 50 60
Days
0.00.20.40.60.81.0
CumulativeIncidenceofNeutrophilRecovery
Group 1
Group 2
Group 3
Neutrophil Engraftment-
MAC sUCBT and dUCBT in adults with AL in CR1
Cumulative incidence (CI) of 60 day
neutrophil recovery: 87±3%
Median time: 22 (10-82)
days
Group 1: sUCBT-CyTBI12: 82±4%, n=68
Group 2: sUCBT-BuFluTT+ATG: 87±4%, n=88
Group 3: dUCBT-CyFluTBI12: 89±32, n=83
32. 0 10 20 30 40 50 60
Months
0.00.20.40.60.81.0
CumulativeIncidenceofRelapse
Group 1
Group 2
Group 3
Relapse at 2-year-
MAC sUCBT and dUCBT in adults with AL in CR1
CI of relapse: 19±3%
Group 1: sUCBT-CyTBI12: 25±4%, n=68
Group 2: sUCBT-BuFluTT+ATG: 18±3%, n=88
Group 3: dUCBT-CyFluTBI12: 16±3%, n=83
No factors associated with RI
in the multivariate analysis
33. TRM at 1-year-
MAC sUCBT and dUCBT in adults with AL in CR1
CI of TRM: 33±3%
Group 1: sUCBT-CyTBI12: 38±6%, n=68
Group 2: sUCBT-BuFluTT+ATG: 33±4%, n=88
Group 3: dUCBT-CyFluTBI12: 29±3%, n=83
0 2 4 6 8 10 12
Months
0.00.20.40.60.81.0
CumulativeIncidenceofTRM
Group 1
Group 2
Group 3
34. Outcomes, MAC sUCBT and dUCBT
in adults with AL in CR1
Outcome
Group 1, sUCBT
TBI-based+Cy
n=68
Group 2, sUCBT
Bu+Flu+Thio
n=88
Group 3, dUCBT
Cy+TBI+Flu
n=83
p value
Neutrophil
Recovery
82±3% 89±2% 87±4% 0,001
Grade II- IV
acute GVHD
30±3% 20±3% 45±3% 0, 001
Chronic GVHD 27±4% 29±5% 29±4% 0,34
2-year Relapse
Incidence
25±4% 18±3% 16±3% 0,22
1-year NRM 44±4% 33±4% 36±4% 0, 46
2-year LFS 30±7% 46±6% 48±4% 0, 005
35. p=0.03
Group 1: sUCBT-CyTBI12: 30±7%, n=68
Group 2: sUCBT-BuFluTT+ATG: 46±6%, n=88
Group 3: dUCBT-CyFluTBI12: 48±6%, n=83
LFS at 2-year-
MAC sUCBT and dUCBT in adults with AL in CR1
36. ALL
diagnosis
HR 1,45- 95%CI 1,3- 2
p=0.04
Age>35y
HR 1,45 -95%CI 1,16- 2,06
p=0,04
Group1 CT:
sUCBT-
CyTBI12
HR 1,62 -95%CI 1,18- 2,52,
p=0,03
Factors associated with lower LFS
LFS – Multivariate analysis
MAC sUCBT and dUCBT in adults with AL in CR1
37. • Overall Survival • Causes of death, n=106
OS at 2-year-
MAC sUCBT and dUCBT in adults with AL in CR1
Group 1: sUCBT-CyTBI12: 33±6%, n=68
Group 2: sUCBT-BuFluTT+ATG: 53±6%, n=88
Group 3: dUCBT-CyFluTBI12: 56±6%, n=83
0 5 10 15 20 25 30 35 40
Interstitial pneumonitis
VOD
Hemorrhage
Rejection
Cardiac toxicity
ARDS
Unknown
Multiorgan failure
infections
Relapse
GvHD
No statistical difference by causes of deaths
among the 3 groups, p= 0.45
38. UCBT after Myeloblative Conditioning regimen
Comparison after single UCB intrabone injection and
dUCBT in patients with hematological malignant
disorders.
An Eurocord-EBMT analysis
Vanderson Rocha, Myriam Labopin, Annalisa Ruggeri, Marina Podestà,
Dolores Caballero, Francesca Bonifazi, Rovira Montserrat, Andrea Gallamini,
Gerard Socie, E Nikiforakis, Mauricette Michalet, E Deconinck,
Mohamad Mohty, Andrea Bacigalupo, Eliane Gluckman,and Francesco Frassoni
Transplantation 2013
39. 10 20 30 40 50 60
0.00.20.40.60.8
IB-CBT N=87
Median days: 23
d-UCBT N=149
Median days: 28
P=0.001
90%
90%
days
Intrabone single UCBT (IB-CBT) versus DoubleUCBT (d-UCBT) after MAC in
patients with hematological malignancies
Cumulative Incidence of PMN recovery (>= 500)
40. 0 30 60 90 120 150 180
0.00.20.40.60.8Cumulative Incidence of Platelets recovery (>=20.000)
81%
65%
P<0.001
days
IB-CBT N=87
d-UCBT N=149
Intrabone single UCBT (IB-CBT) versus DoubleUCBT (d-UCBT) after MAC in
patients with hematological malignancies
42. Outcomes After Double UCBT Compared with
Single UCBT in Adults
with Acute Leukemia in Remission after
Reduced Intensity Conditioning Regimen
43. Comparative Retrospective Registry
Based Analysis
Selection criteria
• First single or double UCBT performed in transplant centers in Europe
• Adults ≥ 18 years old with AML or ALL in CR
• Single CBU with adequate TNC at collection (>2.5x10e7/Kg)
• Reduced intensity conditioning regimen
• From 2005-2011, 360 patients (229 dUCBT and 131 sUCBT)
were transplanted in 10 countries (63 transplant centers)
• AML, n=283, ALL, n=77
• CR1, n=212, CR2, n=148
45. sUCBT dUCBT p
N 76 136
Age (y) Median 52 52 0.6
Range 18-67 18-67
Weight (Kg) Median 64 67 0.07
Range 42-100 40-100
Female Gender 60% 51% 0.05
CMV + 68% 60% 0.86
Median year of UCBT 2008 2009 0.03
RIC –dUCBT versus sUCBT in AL CR1
Patients characteristics
46. N 76 136
Conditioning
CyFluTBI2Gy 68% 87% <0.001
ATG/ALG 35% 21% 0.04
GVHD Prophylaxis <0.001
CsA +MMF+ Corticosteroids 78% 88%
Median follow-up time (mo) 23 (1-86) 23 (1-73)
RIC –dUCBT versus sUCBT in AL CR1
Transplant Characteristics
sUCBT dUCBT p
47. N 76 136
HLA match 0.8
(HLA-A,-B by serology and DRB1 low resolution)
6/6 or 5/6 26% 28%
4/6 or 3/6 74 % 72%
Nucleated cells at collection x107/kg 3.9 5 <0.001
Range 2.6- 6.4 2.9- 9.4
Nucleated cells at infusion x107/kg 3.1 4 <0.001
Range 1.1- 6.5 1.1-9.4
RIC –dUCBT versus sUCBT in AL CR1
Donor characteristics
sUCBT dUCBT p
49. RIC sUCBT versus dUCBT for adults with AL in CR1
Neutrophil recovery
76± 2%
82 ± 3%dUCBT, n=136
sUCBT, n=76
p=0.86
Chimersim Full donor
sUCBT 85%
dUCBT 81% p=0.6
50. RIC sUCBT versus dUCBT for adults with AL in CR1
100 day CI of Acute GVHD II-IV
35± 5%
35 ± 4%
p=0.92
dUCBT, n=136
sUCBT, n=76
51. RIC sUCBT versus dUCBT for adults with AL in CR1
Acute GVHD II-IV
Single UCBT, n=76 Double UCBT, n=136
0
50%
I
14%
II
17%
III
12%
IV
7%
0
46%
I
16%
II
28%
III
8%
IV
2%
grade III-IV, p=0.06
52. RIC sUCBT versus dUCBT for adults with AL in CR1
Acute GVHD II-IV
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Single Double Single Double Single Double
Grade IV
Grade III
Grade II
Grade I
Grade 0
Skin Liver GI
53. RIC sUCBT versus dUCBT for adults with AL in CR1
2-year CI of Chronic GVHD
12± 5%
21± 4%
p=0.15
dUCBT, n=136
sUCBT, n=76
54. RIC sUCBT versus dUCBT for adults with AL in CR1
2 years Non-Relapse Mortality
30 ± 6%
28 ± 4%
p=0.87
dUCBT, n=136
sUCBT, n=76
55. RIC sUCBT versus dUCBT for adults with AL in CR1
2 years Relapse incidence
38 ± 6%
21 ± 4%
p=0.03
In a multivariate analysis adjusted for differences and risk factors
Double CBT was associated with decreased relapse [p=0.01 HR=0.74 (0.58-0.93)]
dUCBT, n=136
sUCBT, n=76
56. 2 years- LFS after RIC sUCBT and dUCBT
in adults with AL in CR1
32 ± 3%
51 ± 5%
p=0.03
In a multivariate analysis adjusted for differences and risk factors
Double CBT was associated with improved LFS rates [p=0.04 HR=0.64 (0.41-0.99)]
dUCBT, n=136
sUCBT, n=76
57. 2 years- LFS after RIC sUCBT and dUCBT
in adults with AL in CR2, n=148
48 ± 3%
40 ± 6%
p=0.32
dUCBT, n=93
sUCBT, n=55
59. Algorithm for UCBT in adults by cell dose, disease
and type of conditioning
• If a single cord blood unit contains < than 2.5x107/kg
1) Double UCBT
2) Intrabone injection (in MAC)
3) Other protocols
(intrabone injection, haplo-cord, expansion…
but minimum cell dose has to be determine 1.5x107/kg)
• If single unit > 2.5x107/kg , and MAC, BU+TT+FLU+ATG
is a good option
• If single unit (> 2.5x107/kg) patients with 1CR, probably
double UCBT is better with the aim to decrease relapse.
Should we intensify the conditioning regimen?
60. Summary
• Use of two partially HLA mismatched UCB units has
extended transplantation to larger recipients that
would otherwise be denied transplantation for lack
of an UCB donor.
• Single ( cell dose and IvBU+TT+FLU) and double have
similar outcomes in MAC, however the use of double
in RIC using the TBI+CY+FLU seems better in AL CR1
• Delayed engraftment requires further research to
reduce its associated NRM
• Additional studies are needed to better understand
the biology of the low relapse rate in recipients of 2
UCB units.
61. Eliane Gluckman MD FRCP
Project Leader
Vanderson Rocha
MD, PhD
Scientific Director
Annalisa Ruggeri, MD
Federica Giannotti , MD
Myriam Pruvost, PA
Fernanda Volt, MT
Chantal Kenzey
Data Manager
EUROCORD TEAM
2012-2013
Erick Xavier, MD
Luciana Tucunduva
MD