Vanderson Rocha, MD, PhD
Professor of Haematology- Oxford University
BMT unit, Churchill Hospital
Oxford, UK
Scientific Di...
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 ...
0
50
100
150
200
250
300
350
400
450
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
...
Double UCBT in children
Preliminary Analysis
Patient characteristics
(n=218)
Patient Characteristics Range
Median age, years
13 y 0.6-18
Median weight, kg
45 Kg ( 25-7...
Diagnosis
Malignant diseases – disease status at UCBT
•Early: 31%
• Intermediate: 31%
•Advanced: 15%
Characteristic range
Conditioning MAC 76%
RIC 24%
GvHD prophylaxis CsA+MMF 48%
CsA+steroids 30%
CsA+MMF+other 5%
FK506+oth...
Neutrophil Engraftment
at 60 days: 87%, n=218
Malignant disease: 90%, n=178, Non Malignant disease: 67%, n=40, p=0.001
Chi...
Non engraftment
• 36 patients experienced primary graft failure
– 27 died in a median time of 72 days after CBT. 5
had rec...
aGvHD grade II-IV
MAC: 42%, n=164
RIC: 34%, n=51
p=0.32
• 100 patients presented grade III-IV
aGvHD
Acute leukemia: relapse
AML, n=48: 37%
ALL, n=101: 25%
p=0.19
Overall Survival
Non Malignant, n=40: 44%
Malignant, n=178: 47%
p=0.73
Overall Survival for acute leukemia
AML, n=48: 52+8%
ALL, n=101: 44+6%
p=0.54
Double UCBT in adults
Preliminary analysis
Patient characteristics
Patient Characteristics Range
Median age, years
46 y 18-76
Median weight, kg
71 kg 40-171
Median y...
Diagnosis (n= 1118)
Malignant diseases – disease status at UCBT
•Early : 25%
•Intermediate : 23%
•Advanced: 38%
Non-malign...
Transplantation and graft characteristics
(n= 1118)
Characteristic range
Conditioning RIC 67%
MAC 33%
GvHD prophylaxis CsA...
Neutrophil Engraftment
(n= 1118)
Neutophil Engraftment at 60 days: 87+1%, n=1118
Chimerism at 100 days available for 881/1...
aGvHD grade II-IV
(n= 1118)
BY HLA COMPATIBILITY BY CONDITIONING REGIMEN
2 HLA MM: 42+2%, n=666
0-1 HLA MM: 34+2%,
n=274
p...
Relapse
(n= 1118)
ACUTE LEUKEMIA OTHER
MALIGNANCIES
N CI N CI
EARLY 267 21% 34 21%
INTERMEDIATE 242 29% 43 21%
ADVANCED 11...
Mortality and causes of death
(n= 681 out 1118)
Among 395 patients transplanted with advanced disease, 267 died in a media...
Disease free Survival
Adults with malignancies (n= 1118)
p<0.001
Lymphoid Mal, n=219: 43+4%
Ac Leukemia, n=820: 39+2%
MDS/...
DFS at 2 year by type of disease and
conditioning regimen
MAC, n=388 RIC, n=711
Lymphoid Mal, n=26:40+11%
Ac Leukemia, n=2...
DFS at 2 year by disease status and conditioning
regimen
MAC, n=388 RIC, n=711
Early , n=147: 44+5%
Intermediate, n=115: 3...
DFS- Multivariate analysis
HR 95%CI p value
Diagnosis: MDS vs acute
leukemia
1.4 1.5- 1.95 0.02
Diagnosis:
Lymphoid malign...
Disease free Survival for acute leukemia
(n=811)
• DFS at 2 year by type of disease
p=0.48
AML, n=499: 40+2%
ALL, n=313: 3...
Disease free Survival for acute leukemia
(n=811)
DFS at 2 year by disease
status, CR1
DFS at 2 year by disease
status, CR2...
Which are the risk factors associated with
the double graft that can change one or
two units selection in dCBT ?
Risk factors of engraftment in dBCT
• Winner unit
dose of CD3 cells?
order of infusion?
CD34 viable cells?
HLA?
others?
• ...
Is there a number of nucleated cells or
CD34 associated with outcomes in double
UCBT?
Patients and disease characteristics
n= 430
Median (range) n
Children 41 (9%)
430
Adult 389 (91%)
Age (years)
Children 15 ...
*HLA A, B antigenic level - DRB1 allelic level
Transplant and Graft Characteristics
n=430
Median (range) n
Conditioning Mi...
Double UCBT (n=430) - Neutrophil Engraftment at 60 days
Number of pfCD34+
• CI Neutrophil Engraftment (NE): 81±2%
• 346 pt...
Double UCBT (n=430)- Neutrophil Engraftment at 60 days
Number of ptCD34+ Number of ptCD34+
0 10 20 30 40 50 60
Days
0.00.2...
0 20 40 60 80 100
Days
0.00.20.40.60.81.0
Cumulativeincidenceoftransplantation-relatedmortality
Double UCBT – TRM at 100 d...
Multivariate analysis -Double UCBT
Summary
pf TNC pfCD34+ pt TNC pt CD34+ Others variables
Overall survival
- - - -
Diseas...
Conclusions
• Double Cord Blood Transplantation has extended the use
of Cord Blood Cells for Adults for whom the number of...
Acknowledgments
EBMT, CIBMTR
Transplant Centers
(Data Managers, Nurses and Physicians)
Cord Blood Banks and Netcord
Eliane Gluckman MD FRCP
Project Leader
Vanderson Rocha
MD, PhD
Scientific Director
Annalisa Ruggeri, MD
Federica Giannotti...
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Outcomes of Double Unit Cord Blood Transplantation in Patients with Malignant Disorders: Eurocord Registry Analysis

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Outcomes of Double Unit Cord Blood Transplantation in Patients with Malignant Disorders: Eurocord Registry Analysis

  1. 1. Vanderson Rocha, MD, PhD Professor of Haematology- Oxford University BMT unit, Churchill Hospital Oxford, UK Scientific Director of Eurocord Paris, France Outcomes of Double Unit Cord Blood Transplantation in patients with malignant disorders: Eurocord Registry analysis
  2. 2. 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%
  3. 3. 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
  4. 4. 0 50 100 150 200 250 300 350 400 450 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 MAC n=4674 RIC n=2629 * Still collecting data Type of Conditioning Regimen per Year * *
  5. 5. Double UCBT in children Preliminary Analysis
  6. 6. Patient characteristics (n=218) Patient Characteristics Range Median age, years 13 y 0.6-18 Median weight, kg 45 Kg ( 25-76) Median year of transplant 2009 2002-2012 Median follow-up 21 months 3-111
  7. 7. Diagnosis Malignant diseases – disease status at UCBT •Early: 31% • Intermediate: 31% •Advanced: 15%
  8. 8. Characteristic range Conditioning MAC 76% RIC 24% GvHD prophylaxis CsA+MMF 48% CsA+steroids 30% CsA+MMF+other 5% FK506+other 4% Other 13% Use of ATG Yes 68% No 32% Number of HLA mismatches 0 5% 1 37% ≥2 58% Median collected TNC, x105/kg 5.1 2.15-44.29 Median infused TNC, x107/kg 5.1 0.98-34.2 Transplant and graft characteristics
  9. 9. Neutrophil Engraftment at 60 days: 87%, n=218 Malignant disease: 90%, n=178, Non Malignant disease: 67%, n=40, p=0.001 Chimerism at 100 days available for 146/182 patients who engrafted, Mixed 10%, Full donor 90% (17 patients had long term persistance of both CBU)
  10. 10. Non engraftment • 36 patients experienced primary graft failure – 27 died in a median time of 72 days after CBT. 5 had received a 2nd Tx (2 haplo, 2 dUCBT, 1 PBSC) – 9 are alive with a median FU of 18 months. 3 with available information, had a subsequent Tx (2 CBT and 1 UD-BMT).
  11. 11. aGvHD grade II-IV MAC: 42%, n=164 RIC: 34%, n=51 p=0.32 • 100 patients presented grade III-IV aGvHD
  12. 12. Acute leukemia: relapse AML, n=48: 37% ALL, n=101: 25% p=0.19
  13. 13. Overall Survival Non Malignant, n=40: 44% Malignant, n=178: 47% p=0.73
  14. 14. Overall Survival for acute leukemia AML, n=48: 52+8% ALL, n=101: 44+6% p=0.54
  15. 15. Double UCBT in adults Preliminary analysis
  16. 16. Patient characteristics Patient Characteristics Range Median age, years 46 y 18-76 Median weight, kg 71 kg 40-171 Median year of transplant 2009 1999-2012 Median follow-up 23 months 3-98 From 1999 to 2012, 1118 adult patients were transplanted with double UCBT In 32 EBMT countries
  17. 17. Diagnosis (n= 1118) Malignant diseases – disease status at UCBT •Early : 25% •Intermediate : 23% •Advanced: 38% Non-malignant: 39/46 BMF
  18. 18. Transplantation and graft characteristics (n= 1118) Characteristic range Conditioning RIC 67% MAC 33% GvHD prophylaxis CsA+MMF 73% CsA+steroids 13% CsA+MMF+other4% FK506+other 3% Other 7% Use of ATG Yes 38% No 62% Number of HLA mismatches 0/1 28% ≥2 72% Median collected TNC, x105/kg 4.9 1.5-14.8 Median infused TNC, x107/kg 3.8 0.33-14.6
  19. 19. Neutrophil Engraftment (n= 1118) Neutophil Engraftment at 60 days: 87+1%, n=1118 Chimerism at 100 days available for 881/1053 patients who engrafted, Mixed 14%, Full donor 86% Lymphoid Mal, n=219: 89+2% Ac Leukemia, n=820: 87+2% MDS/MPS, n=239: 82+3%
  20. 20. aGvHD grade II-IV (n= 1118) BY HLA COMPATIBILITY BY CONDITIONING REGIMEN 2 HLA MM: 42+2%, n=666 0-1 HLA MM: 34+2%, n=274 p=0.25 MAC, n=350:34+2% RIC, n=660: 32+2% p=0.32
  21. 21. Relapse (n= 1118) ACUTE LEUKEMIA OTHER MALIGNANCIES N CI N CI EARLY 267 21% 34 21% INTERMEDIATE 242 29% 43 21% ADVANCED 114 39% 281 30%
  22. 22. Mortality and causes of death (n= 681 out 1118) Among 395 patients transplanted with advanced disease, 267 died in a median time of 108 days after CBT, of those 106, of the original disease
  23. 23. Disease free Survival Adults with malignancies (n= 1118) p<0.001 Lymphoid Mal, n=219: 43+4% Ac Leukemia, n=820: 39+2% MDS/MPS, n=239: 27+3%
  24. 24. DFS at 2 year by type of disease and conditioning regimen MAC, n=388 RIC, n=711 Lymphoid Mal, n=26:40+11% Ac Leukemia, n=286: 34+2% MDS/MPS, n=72: 25+3% Lymphoid Mal, n=181: 41+3% Ac Leukemia, n=371: 41+3% MDS/MPS, n=151: 23+4%
  25. 25. DFS at 2 year by disease status and conditioning regimen MAC, n=388 RIC, n=711 Early , n=147: 44+5% Intermediate, n=115: 36+5% Advanced n=120: 18+4% Early , n=224 46+5% Intermediate, n=215: 44+4% Advanced n=264: 27+4%
  26. 26. DFS- Multivariate analysis HR 95%CI p value Diagnosis: MDS vs acute leukemia 1.4 1.5- 1.95 0.02 Diagnosis: Lymphoid malignancies vs acute leukemia 1.2 0.88- 1.7 0.22 Disease Status Remission vs not remission 0.51 0.38- 0.68 0.0001
  27. 27. Disease free Survival for acute leukemia (n=811) • DFS at 2 year by type of disease p=0.48 AML, n=499: 40+2% ALL, n=313: 37+2%
  28. 28. Disease free Survival for acute leukemia (n=811) DFS at 2 year by disease status, CR1 DFS at 2 year by disease status, CR2 AML, n=196: 50+4% ALL, n=136: 48+2% AML, n=175: 48+4% ALL, n=129: 38+2%
  29. 29. Which are the risk factors associated with the double graft that can change one or two units selection in dCBT ?
  30. 30. Risk factors of engraftment in dBCT • Winner unit dose of CD3 cells? order of infusion? CD34 viable cells? HLA? others? • Engraftment Disease status? Conditioning regimen? Cell dose? TNC? CD34? CFU-GM?
  31. 31. Is there a number of nucleated cells or CD34 associated with outcomes in double UCBT?
  32. 32. Patients and disease characteristics n= 430 Median (range) n Children 41 (9%) 430 Adult 389 (91%) Age (years) Children 15 (4-18) 41 Adult 45 (18-67) 389 Weight (Kg) Children 52 (14-88) 41 Adult 70 (40-120) 389 Positive CMV serology 205 (49%) 413 Diagnosis 241 (56%) 430 Acute leukemia 58 (13%) MDS 131 (31%) Other malignancies Advanced Diseases 168 (40%) 419 Median Follow up (months) 12 (3-70)
  33. 33. *HLA A, B antigenic level - DRB1 allelic level Transplant and Graft Characteristics n=430 Median (range) n Conditioning Mieloablative 126 (30%) 418 GVHD Prophylaxis 418CsA + Steroids 39 (9%) CsA + MMF 307 (78%) ALG/ATG before day 0 78 (22%) 395 HLA Matching * 428 6/6 5 (1%) 5/6 102 (24%) 4/6 297 (70%) Pre-freezing (pf) 430TNC (x107 /Kg) 4.7 (2-27) CD34 (x105 /Kg) 1.7 (0.3-10) Post-thawing (pt) 430TNC (x107 /Kg) 3.5 (0.8-22) CD34 (x105 /Kg) 1.2 (0.2-7)
  34. 34. Double UCBT (n=430) - Neutrophil Engraftment at 60 days Number of pfCD34+ • CI Neutrophil Engraftment (NE): 81±2% • 346 pts (80%) achieved engraftment in a median time of 23 days 0 10 20 30 40 50 60 Days 0.00.20.40.60.81.0 Cumulativeincidenceofneutrophilengraftment pf CD34 <1.7x105/kg 79+3% pf CD34 >1.7x105/kg 83+3% p = 0.03
  35. 35. Double UCBT (n=430)- Neutrophil Engraftment at 60 days Number of ptCD34+ Number of ptCD34+ 0 10 20 30 40 50 60 Days 0.00.20.40.60.81.0 Cumulativeincidenceofneutrophilengraftment ptCD34 < 1.2x05/kg 76+3% ptCD34 > 1.2x05/kg 85+2% p = 0.04 0 10 20 30 40 50 60 Days0.00.20.40.60.81.0 Cumulativeincedenceofneutrophilengraftment p = 0.006 ptCD34 < 0.9x05/kg 74+4% ptCD34 > 0.9 and < 1.8 x05/kg 81+3% ptCD34 > 1.8x105/kg 87+3%
  36. 36. 0 20 40 60 80 100 Days 0.00.20.40.60.81.0 Cumulativeincidenceoftransplantation-relatedmortality Double UCBT – TRM at 100 days CI 12 months of TRM: 16+2 % pfCD34 > 1.2x05/kg 11+2% pfCD34 <1.2x05/kg 18+3% p = 0.02 Number of pfCD34+ 0 20 40 60 80 100 Days 0.00.20.40.60.81.0 Cumulativeincidenceoftransplantantion-relatedmortality
  37. 37. Multivariate analysis -Double UCBT Summary pf TNC pfCD34+ pt TNC pt CD34+ Others variables Overall survival - - - - Disease status at transplantation Disease free survival - - - - Disease status at transplantation Neutrophil engraftment - 1.7x105 /kg (median) - 1.2x105 /kg (4th percentile) No other factor p=0.04 p=0.015 Transplantation-related mortality - 1.2X105 /kg (4th percentile) - HLA, MAC, age p=0.004
  38. 38. Conclusions • Double Cord Blood Transplantation has extended the use of Cord Blood Cells for Adults for whom the number of cells is not sufficient. • Need of more data and follow-up • However despite a higher cell dose, graft failure is around 10-15% (a higher CD34+ cell dose of both units seems to be an important factor to increase engraftment and decrease mortality) • Acute GVHD seems to be increased • Mortality is associated with infections (delayed engraftment?, delayed immune recovery?), GVHD and toxicity • MDS and advanced disease are factors associated with decreased DFS rates
  39. 39. Acknowledgments EBMT, CIBMTR Transplant Centers (Data Managers, Nurses and Physicians) Cord Blood Banks and Netcord
  40. 40. 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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