Outcomes Using Single and Double Unit
Cord Blood Transplant Grafts
Vanderson Rocha, MD, PhD
Eurocord
Hôpital Saint Louis, ...
Overcoming the Cell Dose Limitation
If no single graft is big enough then …
HLA A & B: Ag level
HLA DRB1: Allele level
4/6...
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-...
Eurocord Registry
General data base* overview
*Eurocord Registry status as off December, 31st, 2012
Eurocord registry data...
Eurocord Registry at ABM
Unrelated European CBT by recipient’s age and graft type
Children Adults
* Still collecting 2012 ...
Should Transplantation of Two Cord
Blood Units be the Standard for
Adults?
 Approximately 80 - 85% of cord blood
transpla...
Should Transplantation of Two Cord
Blood Units be the Standard for
Adults?
 Ideal study design
 Randomized trial
 Each ...
Minnesota Studies
• Double UCBT promotes engraftment, achieving
rates comparable to single UCBT with adequate
cell doses: ...
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 ...
Other studies in USA and Europe?
Study Design
 Used data reported to observational
registries
 CIBMTR; N = 327
 NYBC; N = 79
 All single units containe...
Study Population
 N = 303 recipients of double UCBT
 N = 106 recipients of single UCBT
 AML or ALL
 Transplant period:...
Neutrophil Recovery
- Adequate Dose Single vs. Double UCBT -
Incidence,%
Months
0 1 2 643
100
0
20
40
60
80
0
100
20
40
60...
Grade II-IV Acute GVHD
- Adequate Dose Single vs. Double UCBT -
Incidence,%
Months
0 2 4 1286
100
0
20
40
60
80
0
100
20
4...
Chronic Graft vs. Host Disease
- Adequate Dose Single vs. Double UCBT -
Incidence,%
Months
0 6 12 362418
100
0
20
40
60
80...
Transplant-related Mortality
- Adequate Dose Single vs. Double UCBT -
Incidence,%
Months
0 6 12 362418
100
0
20
40
60
80
0...
Relapse
- Adequate Dose Single vs. Double UCBT -
Incidence,%
Months
0 6 12 362418
100
0
20
40
60
80
0
100
20
40
60
80
Doub...
Relapse
- Myeloablative Conditioning -
Incidence,%
Months
0 6 12 362418
100
0
20
40
60
80
0
100
20
40
60
80
30
SUCBT, adva...
Relapse
- Reduced Intensity Conditioning -
Incidence,%
Months
0 6 12 362418
100
0
20
40
60
80
0
100
20
40
60
80
30
Single ...
Overall Survival
- Adequate Dose Single vs. Double UCBT -
AdjustedProbability,%
Months
0 6 12 362418
100
0
20
40
60
80
0
1...
SUMMARY
 These data confirm
 Infusing 2 UCB units overcomes the cell
dose barrier
 Thereby making this treatment access...
Outcomes After Double Unit Unrelated Cord Blood
Transplantation (UCBT) Compared with Single UCBT in
Adults
with Acute Leuk...
Double versus Single UCBT in Adults with AL
by conditioning regimen
Selection criteria
• First single or double UCBT perfo...
Outcomes After Double UCBT Compared with
Single UCBT in Adults
with Acute Leukemia in Remission after
Myeloablative Condit...
Selection Criteria
• Adult patients with ALL and AML, in CR1
•UCBT from 2005 to 2011 in EBMT centers
• Single and double U...
Patients and disease characteristics, n=239
Patients Characteristics AL in CR1, n=239
Median Follow-up 24 (3-74) months
Me...
Characteristics, n=239
• Pts were transplanted with sUCBT (n=156) or dUCBT
(n=83)
• Type of MAC was statistically associat...
Type of Graft and Conditioning Regimen, n=239
Graft Characteristics
Group 1, sUCBT
TBI-based+Cy
n=68
Group 2, sUCBT
Bu+Flu...
0 10 20 30 40 50 60
Days
0.00.20.40.60.81.0
CumulativeIncidenceofNeutrophilRecovery
Group 1
Group 2
Group 3
Neutrophil Eng...
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 ...
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: ...
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...
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
...
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%...
• Overall Survival • Causes of death, n=106
OS at 2-year-
MAC sUCBT and dUCBT in adults with AL in CR1
Group 1: sUCBT-CyTB...
UCBT after Myeloblative Conditioning regimen
Comparison after single UCB intrabone injection and
dUCBT in patients with he...
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 ...
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=...
Disease Free Survival
months
47%
37%
Intrabone single UCBT (IB-CBT) versus DoubleUCBT (d-UCBT) after MAC in
patients with ...
Outcomes After Double UCBT Compared with
Single UCBT in Adults
with Acute Leukemia in Remission after
Reduced Intensity Co...
Comparative Retrospective Registry
Based Analysis
Selection criteria
• First single or double UCBT performed in transplant...
RIC, Single vs Double UCBT
CR1 n=212
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...
N 76 136
Conditioning
CyFluTBI2Gy 68% 87% <0.001
ATG/ALG 35% 21% 0.04
GVHD Prophylaxis <0.001
CsA +MMF+ Corticosteroids 78...
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 cel...
Results
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
Chimers...
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, ...
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%
...
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 Doubl...
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
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, ...
RIC sUCBT versus dUCBT for adults with AL in CR1
2 years Relapse incidence
38 ± 6%
21 ± 4%
p=0.03
In a multivariate analys...
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...
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
Leukemia-Free Survival
- Double Cord Blood Transplant -
Probability,%
Months
0 6 12 362418
100
0
20
40
60
80
90
10
30
50
7...
Algorithm for UCBT in adults by cell dose, disease
and type of conditioning
• If a single cord blood unit contains < than ...
Summary
• Use of two partially HLA mismatched UCB units has
extended transplantation to larger recipients that
would other...
Eliane Gluckman MD FRCP
Project Leader
Vanderson Rocha
MD, PhD
Scientific Director
Annalisa Ruggeri, MD
Federica Giannotti...
Outcomes Using Single and Double Unit Cord Blood Transplant Grafts
Outcomes Using Single and Double Unit Cord Blood Transplant Grafts
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Outcomes Using Single and Double Unit Cord Blood Transplant Grafts

  1. 1. Outcomes Using Single and Double Unit Cord Blood Transplant Grafts Vanderson Rocha, MD, PhD Eurocord Hôpital Saint Louis, Paris
  2. 2. 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
  3. 3. 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,%
  4. 4. 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%
  5. 5. 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
  6. 6. 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
  7. 7. 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
  8. 8. 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
  9. 9. 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%)
  10. 10. Other studies in USA and Europe?
  11. 11. 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
  12. 12. 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
  13. 13. Neutrophil Recovery - Adequate Dose Single vs. Double UCBT - Incidence,% Months 0 1 2 643 100 0 20 40 60 80 0 100 20 40 60 80Single UCBT, advanced 71% Single UCBT, early/intermediate, 81% Double UCBT, advanced, 65% Double UCBT, early/intermediate, 81% 5 Early/Intermediate: CR1, CR2 Advanced: Relapse
  14. 14. Grade II-IV Acute GVHD - Adequate Dose Single vs. Double UCBT - Incidence,% Months 0 2 4 1286 100 0 20 40 60 80 0 100 20 40 60 80 Double UCBT early period, 58% Single UCBT early period, 18% Double UCBT later period, 31% Single UCBT later period, 27% 10 Early period: 2000-2004 Later period: 2005 -2009 P<0.001
  15. 15. Chronic Graft vs. Host Disease - Adequate Dose Single vs. Double UCBT - Incidence,% Months 0 6 12 362418 100 0 20 40 60 80 0 100 20 40 60 80 Single UCBT, TNC ≥2.5 x 107/kg , 24% Double UCBT, 31% 30 HR 1.33, p=0.27
  16. 16. Transplant-related Mortality - Adequate Dose Single vs. Double UCBT - Incidence,% Months 0 6 12 362418 100 0 20 40 60 80 0 100 20 40 60 80 Single UCBT, TNC ≥2.5 x 107/kg, 38% Double UCBT, 32% 30 HR 0.91, p=0.63
  17. 17. Relapse - Adequate Dose Single vs. Double UCBT - Incidence,% Months 0 6 12 362418 100 0 20 40 60 80 0 100 20 40 60 80 Double UCBT, 36% Single UCBT, TNC ≥2.5 x 107/kg, 32% 30 HR 0.90, p=0.64
  18. 18. Relapse - Myeloablative Conditioning - Incidence,% Months 0 6 12 362418 100 0 20 40 60 80 0 100 20 40 60 80 30 SUCBT, advanced, 42% SUCBT, early/intermediate, 24% DUCBT, advanced, 46% DUCBT, early/intermediate 20% Early/Intermediate: CR1, CR2 Advanced: Relapse
  19. 19. Relapse - Reduced Intensity Conditioning - Incidence,% Months 0 6 12 362418 100 0 20 40 60 80 0 100 20 40 60 80 30 Single UCBT advanced, 67% Single UCBT early/intermediate, 46% Double UCBT advanced, 64% Double UCBT early/intermediate, 48% Early/Intermediate: CR1, CR2 Advanced: Relapse
  20. 20. Overall Survival - Adequate Dose Single vs. Double UCBT - AdjustedProbability,% Months 0 6 12 362418 100 0 20 40 60 80 0 100 20 40 60 80 RR Double UCBT, 32% Single UCBT, TNC ≥2.5 x 107/kg, 33% 30 HR 0.92, p=0.62
  21. 21. 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
  22. 22. 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
  23. 23. 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)
  24. 24. Outcomes After Double UCBT Compared with Single UCBT in Adults with Acute Leukemia in Remission after Myeloablative Conditioning Regimen
  25. 25. 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
  26. 26. 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
  27. 27. 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%
  28. 28. 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).
  29. 29. 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
  30. 30. 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
  31. 31. 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
  32. 32. 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
  33. 33. 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
  34. 34. 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
  35. 35. • 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
  36. 36. 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
  37. 37. 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)
  38. 38. 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
  39. 39. Disease Free Survival months 47% 37% Intrabone single UCBT (IB-CBT) versus DoubleUCBT (d-UCBT) after MAC in patients with hematological malignancies IB-CBT N=87 d-UCBT N=149
  40. 40. Outcomes After Double UCBT Compared with Single UCBT in Adults with Acute Leukemia in Remission after Reduced Intensity Conditioning Regimen
  41. 41. 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
  42. 42. RIC, Single vs Double UCBT CR1 n=212
  43. 43. 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
  44. 44. 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
  45. 45. 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
  46. 46. Results
  47. 47. 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
  48. 48. 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
  49. 49. 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
  50. 50. 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
  51. 51. 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
  52. 52. 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
  53. 53. 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
  54. 54. 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
  55. 55. 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
  56. 56. Leukemia-Free Survival - Double Cord Blood Transplant - Probability,% Months 0 6 12 362418 100 0 20 40 60 80 90 10 30 50 70 0 100 20 40 60 80 90 10 30 50 70 30 MMUD: 25% MUD: 31% dCB, TCF: 26% dCB, other: 9% Brunstein et al; Blood 2012
  57. 57. 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?
  58. 58. 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.
  59. 59. 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

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