Unrelated Cord Blood Transplantation In Adults with Hematological Malignancies Eurocord Results

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Unrelated Cord Blood Transplantation In Adults with Hematological Malignancies Eurocord Results

  1. 1. Vanderson Rocha, MD, PhD Professor of Haematology- Oxford University BMT unit, Churchill Hospital Oxford, UK Scientific Director of Eurocord Paris, France Unrelated Cord Blood Transplantation In adults with Hematological Malignancies Eurocord Results
  2. 2. UCBT for adults with Malignancies • Eurocord Registry update • Indications • Survey on outcomes for specific diseases • Survey on outcomes of elderly patients in Europe and USA • Conditioning regimen • Complications (engraftment)
  3. 3. UCBT for adults with Malignancies • Eurocord Registry update • Indications • Survey on outcomes for specific diseases • Survey on outcomes of elderly patients in Europe and USA • Conditioning regimen • Complications (engraftment)
  4. 4. Eurocord Registry Update • 12.066 CBU shipped for transplantation (283, 2%, not used): 11.783 CBU used for: • 9.883 CBT from 1988 to 2012 in 51 countries and 577 centres 293 EBMT 6958 cases (75%) 267 Non-EBMT 2379 cases (25%) 54% 46% Children n=5071 (54%) Adult n=4265 (46%) 8% 92% Related n=708 (8%) Unrelated n=8618 (92%)
  5. 5. Eurocord Registry N°of European CBUs shipped by year* * 215 CBUs not infused are included in the bar chart 0 100 200 300 400 500 600 700 800 900 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Year of shipment N of CBUs 1990 3 1991 1 1992 2 1993 1 1994 5 1995 15 1996 30 1997 58 1998 92 1999 123 2000 145 2001 192 2002 167 2003 187 2004 298 2005 440 2006 590 2007 695 2008 823 2009 813 2010 878 2011 817 2012 813 N=7188
  6. 6. Eurocord Registry 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. 7. CELL DOSE
  8. 8. Children, n=2354 Adult, n=1337 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% TNC (x10^7) of CBU Used for Single Transplants
  9. 9. UCBT for adults with Malignancies • Eurocord Registry update • Indications • Survey on outcomes for specific diseases • Survey on outcomes of elderly patients in Europe and USA • Conditioning regimen • Complications (engraftment)
  10. 10. Indication for Unrelated UCBT in adults 0 100 200 300 400 500 600 700 21% 39% 14% 8% 1% 12% 2% 3% 17% 37% 14% 5% 4% 15% 4% 4% Single, n= 1735 Double, n= 1752
  11. 11. Age distribution for adult patients 0 200 400 600 800 1000 1200 16- 30 y 30- 39 y 40- 49 y 50- 59 y >60 y 1103 736 790 752 433 N=1185
  12. 12. UCBT for adults with Malignancies • Eurocord Registry update • Indications • Survey on outcomes for specific diseases • Survey on outcomes of elderly patients in Europe and USA • Conditioning regimen • Complications (engraftment)
  13. 13. 2 Years Survival in Adults (single and double unrelated CBT)
  14. 14. 2 Years Survival in Adults (single and double unrelated CBT) with Acute Leukemia (n=1552) by disease status CR1 (n= 636)- 48% CR2 (n= 557)- 41% More advanced (n= 359)-12%
  15. 15. Unrelated CBT- Outcomes and Risk factors for specific diseases
  16. 16. Clinical Results of Unrelated CBT in Adults n Median FU (m/y) Outcomes Favourable Risk Factors Ref Lymphoid malignancies 104 18 m DFS: 41% Chemosensitive disease Low-dose TBI Cell dose>2x107/Kg JCO, 2009 MDS 108 25 m DFS: 30% low-risk disease Leukemia, 2010 Acute leukemia- KIR 218 14 m LFS: KIR-MM: 55% KIR-M: 31% KIR-ligand incompatibility HLA 0/1 mismatch Leukemia 2009 Acute leukemia- RIC 155 18 m LFS: 51% Disease Status HLA 0/1 mismatch Not published ALL 421 24 m LFS CR1: 39% CR2: 31% Adv: 8% Disease Status, age<35 No use of ATG Submitted 2013 AML 604 24 m LFS: CR1: 43% CR2: 38% Adv: 11% Disease Status, no previous autologous transplant, TBF (MAC) Disease status, age<48 years Not published
  17. 17. Clinical Results of Unrelated CBT in Adults n Median FU (m/y) Outcomes Favourable Risk Factors Ref Lymphoid malignancies 104 18 m DFS: 41% Chemosensitive disease Low-dose TBI Cell dose>2x107/Kg JCO, 2009 MDS 108 25 m DFS: 30% low-risk disease Leukemia, 2010 Acute leukemia- KIR 218 14 m LFS: KIR-MM: 55% KIR-M: 31% KIR-ligand incompatibility HLA 0/1 mismatch Leukemia 2009 Acute leukemia- RIC 155 18 m LFS: 51% Disease Status HLA 0/1 mismatch Not published ALL 421 24 m LFS CR1: 39% CR2: 31% Adv: 8% Disease Status, age<35 No use of ATG Submitted 2013 AML 604 24 m LFS: CR1: 43% CR2: 38% Adv: 11% Disease Status, no previous autologous transplant, TBF (MAC) Disease status, age<48 years Not published
  18. 18. Outcomes of unrelated cord blood transplant for adults with acute lymphoblastic leukemia: a survey conducted by Eurocord and the ALWP/EBMT L Tucunduva, A Ruggeri , G Sanz, S Furst, B Rio, G Socié, W Arcese, M Michallet, I Yakoub-Agha, J Cornelissen, J Sanz, P Montesinos, D Purtill, E Gluckman, M Mohty and V Rocha BMT Tandem Meetings CIBMTR / ASBMT Salt Lake City 13-17 February/2013 No conflict of interest to disclose
  19. 19. Patient and disease characteristics n=421 Characteristics CR1, n=195 CR2, n= 136 Not CR n= 90 Median age at UCBT, years (range) 35 (18-64) 26 (18-76) 30 (18-60) Age ≥35 years at diagnosis 48% 25% 31% Immunophenotype B 71% 74% 63% T 20% 21% 35% Other 9% 5% 2% WBC count at diagnosis median (range) 16 (0.6-456) 11 (0.2-624) 13 (0.7-515) ≥30x109 /L 40% 32% 39% ≥100x109 /L 14% 14% 24% Cytogenetics very high risk 57% 23% 28% high risk 5% 2% 8% standard risk 38% 75% 63% Median time from diagnosis to UCBT, months (range) 7 (3-39) 31 (2-96) 16 (3-113) Median time from diagnosis to first relapse, months (range) na 27 (3-140) 13 (2-138)
  20. 20. Transplant characteristics Characteristics CR1, n=195 CR2, n= 136 Not CR n= 90 Type of UCB graft single 57% 54% 70% double 43% 46% 30% TNC x107 /Kg; median (range) 4.0 (1.8-9.4) 4.1 (1.5-9.0) 3.8 (1.8-9.2) HLA matching No mismatch 4% 1% 0% 1 mismatch 32% 23% 26% 2-3 mismatches 64% 76% 74% Type of conditioning RIC 28% 24% 18% MAC 72% 76% 82%
  21. 21. Other n=30 (29%) Cy+Flu+ TBI n=73 (71%) Conditioning MAC n=314 RIC n=103 Cy+TBI n=80 (44%) Cy+Flu +TBI n=63 (35%) Other n=36 Cy+Bu n=10 (8%) Cy+Bu+Thio n=27 (21%) Bu+Flu+Thio n=78 (62%) Other n=11 (9%) Cy+Thio n=1 Cy+Bu+Thio n=1 Cy+Flu n=3 Flu+Mel n= 1 Cy+Flu+Mel n=2 Cy+Flu+Thio n=1Bu+Flu n=1 Cy+Bu+Flu n= 2 Bu+Flu+Thi o n=8 Flu+other n=4 Cy+Bu+Flu+ ARAC+amsa crine n=1
  22. 22. GVHD prophylaxis MAC RIC 0 10 20 30 40 50 60 70 80 0 20 40 60 80 100 120 • Use of ATG in conditioning regimen p<0.0001
  23. 23. Results - 2y LFS all patients CR1 39±4%(n=195) CR2 31±4% (n=136) not in CR 8±3% (n=90) p<0.0001
  24. 24. Results - 2y LFS all patients no ATG 42±4% (n=132) ATG 23±3% (n=239) p<0.0001
  25. 25. Results - 2y LFS MAC RIC no ATG 39±6% (n=72) ATG 23±3% (n=212) no ATG 47±6% (n=62) ATG 33±10% (n=25) p=0.02 p=0.04
  26. 26. Multivariate analysis for LFS • Variables tested in the model: -- age (≥35 vs <35 years) -- remission status (CR1 and CR2 vs advanced) -- median collected TNC (equal or superior vs inferior 4.0x107/kg) -- conditioning (RIC vs MAC) -- type of graft (single vs double) -- use of ATG in conditioning regimen (yes vs no) Variable HR 95% IC p value age ≥35 y 1.3 1.1-1.7 0.03 not in CR at UCBT 2.5 2.0-3.3 <0.0001 ATG 1.5 1.1-2.0 0.009 Factors associated with decreased LFS
  27. 27. Clinical Results of Unrelated CBT in Adults n Median FU (m/y) Outcomes Favourable Risk Factors Ref Lymphoid malignancies 104 18 m DFS: 41% Chemosensitive disease Low-dose TBI Cell dose>2x107/Kg JCO, 2009 MDS 108 25 m DFS: 30% low-risk disease Leukemia, 2010 Acute leukemia- KIR 218 14 m LFS: KIR-MM: 55% KIR-M: 31% KIR-ligand incompatibility HLA 0/1 mismatch Leukemia 2009 Acute leukemia- RIC 155 18 m LFS: 51% Disease Status HLA 0/1 mismatch Not published ALL 421 24 m LFS CR1: 39% CR2: 31% Adv: 8% Disease Status, age<35 No use of ATG Submitted 2013 AML 604 24 m LFS: CR1: 43% CR2: 38% Adv: 11% Disease Status, no previous autologous transplant, TBF (MAC) Disease status, age<48 years Not published
  28. 28. Cord blood transplantation for adult with acute myeloid leukaemia: a survey on behalf of Eurocord and ALWP-EBMT Annalisa Ruggeri, William Arcese, Guillermo Sanz, Bernard Rio, Noel Milpied, Sabine Furst, Josep Ribera, Alberto Bosi, Emmanouel Nikiforakis, Eliane Gluckman, Mohamad Mohty, Myriam Labopin and Vanderson Rocha 16th Congress of the European Hematology Association (EHA) London - 11/06/2011 No conflict of interest to disclose
  29. 29. UCBT for AML Patients and disease characteristics, n= 604 60% single and 40% adults CR1, n=229 CR>=2, n=228 Adv, n=147 Median age at UCBT (years) 40 (18-66) 42 (18-68) 41 (22-67) Male 109 (49%) 109 (48%) 71 (48%) Positive pts CMV serology 130 (63%) 133 (64%) 74 (64%) High risk cytogenetic n=192 n=190 n=114 115 (60%) 94 (49%) 63 (55%) Interval diagnosis-UCBT 6 months 22 months 13 months Previous HSCT (auto/allo) 12 (5%) 77 (34%) 44 (32%) Median Follow-up 24 (range 3-120) months
  30. 30. UCBT for AML Transplant characteristics, n=604 • MAC • RIC MAC: TBI dose > 6Gy, Busulfan dose >8 mg/Kg or IV BU>9.6 mg/kg CyFluTBI- 2Gy 72% Other Flu- Based 15% Other 13%BuFluTT 34% BuCy 10%BuCyTT 5% CYTBI-12Gy 16% CyFluTBI- 12Gy 11% Other Bu- Based 12% Other 12%
  31. 31. UCBT for AML- MAC LFS MAC- 2y LFS by disease status, n=293 Disease Status (Remission) HR 2,11- 95%CI 1,56- 2,87, p=<0,0001 No Previous HSCT HR 2,19 -95%CI 1,58- 3,04, p=<0,0001 Multivariate analysis (LFS- MAC) CR1: 51% CR2 and CR3:37% Adv: 14% p<0.0001
  32. 32. UCBT for AML- RIC LFS RIC- 2y LFS by disease status, n=289 Disease Status (Remission) HR 2,5- 95%CI 1,73- 3,59, p=<0,0001 Age<48y HR 1,45 -95%CI 1,16- 2,06, p=0,02 CyFluTBI2Gy HR 1,67 -95%CI 1,18- 2,37, p=0,004 Multivariate analysis (LFS- RIC) CR2 and CR3 : 47% CR1: 38% Adv: 9%p<0.0001
  33. 33. UCBT for adults with Malignancies • Eurocord Registry update • Indications • Survey on outcomes for specific diseases • Survey on outcomes of elderly patients in Europe and USA • Conditioning regimen • Complications (engraftment)
  34. 34. Changing trends of UCBT for hematological malignancies in patients older than 50 years: a Eurocord- CIBMTR survey Annalisa Ruggeri, Mary Eapen, Luciana Tucunduva, Fernanda Volt, Mary Horowitz, Vanderson Rocha, Daniel Weisdorf and Eliane Gluckman No conflict of interest to disclose
  35. 35. UCBT in Children and Adults per Year 0 100 200 300 400 500 600 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 0 100 200 300 400 500 600 700 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Eurocord, n=9470 CIBMTR, n=9617 Adult, n=4354 Children, n=5116 Adult, n=4019 Children, n=5598
  36. 36. Single and double UCBT: distribution of age for adult patients 0 200 400 600 800 1000 1200 16- 30 y 30- 39 y 40- 49 y 50- 59 y >60 y 1171 780 719 805 477 1103 736 790 752 433 Eurocord CIBMTR
  37. 37. Study Objective Survey of patients more than 50 years of age reported to Eurocord and CIBMTR • Period 2005 - 2011 • Hematologic malignancies N = 1529 n = 848 (N. America) n= 681 (Europe) Median follow up: 24 months 0 100 200 300 400 500 600 50- 59 y 60- 69 y 70+ y Eurocord CIBMTR 64% 36% 60% 37% 3% Age distribution
  38. 38. 8% 42% 20% 3% 6% 12% 7% 1% 1% 8% 52%14% 3% 8% 14% 1% ALL AML MDS/MPD CML CLL NHL HD PCD Solid Tumor BMFS Diagnosis Eurocord CIBMTR
  39. 39. Transplant characteristics Graft Type Conditioning Regimen 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Eurocord, n=681 CIBMTR, n=848 Double UCBT Single UCBT 0% 50% 100% 50- 59 y- CIBMTR 50- 59 y- Eurocord 60- 69 y- CIBMTR 60- 69 y- Eurocord 52% 77% 72% 93% 48% 23% 21% 7% ■ RIC ■ MAC 29% 71% 39% 61%
  40. 40. Overall Survival - Acute Myeloid Leukemia - Eurocord, n=262 42±5% 40±6% 11±5% ■ CR1, n=117 ■ CR2, n=91 ■ Advanced, n=154
  41. 41. Overall Survival - Acute Myeloid Leukemia - Probability,% Years 0 100 0 20 40 60 80 90 10 30 50 70 0 100 20 40 60 80 90 10 30 50 70 1 2 CR1 (N=213) CR2 (N=107) Relapse (N=89) CIBMTR, n=409
  42. 42. Overall Survival -AML by disease status and conditioning- Eurocord, n=257 46±4% 33±10% 30±12% 6±4% ■ CR and MAC, n=29 ■ CR and RIC, n=176 ■ Rel and MAC, n=17 ■ Rel and RIC, n=35
  43. 43. Overall Survival - Acute Myeloid Leukemia – Probability,% Years 0 100 0 20 40 60 80 90 10 30 50 70 0 100 20 40 60 80 90 10 30 50 70 1 2 CR and MAC (N=112) CR and RIC (N=191) Rel and MAC (N=49) Rel and RIC (N=31) CIBMTR, n=373
  44. 44. Overall Survival - Myelodysplastic Syndrome - Eurocord, n=138 28±6% 25±6% ■ 50-59 yrs, n=83 ■ +60 yrs, n=55
  45. 45. Overall Survival - Myelodysplastic Syndrome - Probability,% Years 0 100 0 20 40 60 80 90 10 30 50 70 0 100 20 40 60 80 90 10 30 50 70 1 2 50-59 yrs (N=62) 60+ yrs (N=44) CIBMTR, n=106
  46. 46. UCBT for adults with Malignancies • Eurocord Registry update • Indications • Survey on outcomes for specific diseases • Survey on outcomes of elderly patients in Europe and USA • Conditioning regimen • Complications (engraftment)
  47. 47. 0 50 100 150 200 250 300 350 1990 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Type of Conditioning Regimen in Single and Double UCBT Single UCBT, n=4946 Double UCBT, n=1841 * * Still collecting data MAC n=3581 RIC n=1365 MAC n=644 RIC n=1197 *
  48. 48. No Flu Based (n=1471) 86 % Fludarabine based MAC (n=384) 91% 6050403020100 1,0 ,8 ,6 ,4 ,2 0,0 Neutrophil recovery after single UCBT for patients with malignant disorders after myeloablative conditioning regimen (n=1946) p< 0.0001
  49. 49. Conditioning regimen Myeloablative Analyze the impact of TT, iv BU, F+ATG (TBF-ATG) on long term outcomes after single unit UCBT compared to other MAC regimens in adults with leukemias in remission H Bittencourt et al. # 377, Oral session EBMT
  50. 50. Thiotepa-Busulfan-Fludarabine versus Cyclophosphamide-based Myeloablative Conditioning Regimen In Remission
  51. 51. Early Stage (n=147) Characteristics Group 1, sUCBT Cy-based n=93 Group 2, sUCBT Bu+Flu+TT n=54 Age (years) 33(18-54) 32 (19-51) HLA match – 4/6 51(56%) 28(53%) Acute Leukemia* 79(85%) 52 (96%) Median TNC after thawing (107 Kg) 2.5 (0.6-7.6) 2.3 (1.4-4.9) GVHD Prophylaxis: CSA+Steroids ATG 78(84%) 83(89%) 38 (70%) 48(89%) Year of UCBT* 2003 (2000-2007) 2006 (2005-2008) * P<0.05 Besides ABO major incompatibility (P=0.02), there was no other differences among the 2 groups for patients disease and UCBT characteristics (gender, weight, CMV status, previous autologous HSCT, CD34+ infused cells)
  52. 52. EFS at 5 years Early Stage Group 1: sUCBT-Cy-based: 28% Group 2: sUCBT-BuFluTT: 41% BuFluTT associated with better event-free survival in multivariate analysis HR 0.64 (CI95%:0.41-0.99 – P=0.04) P=0.07 DFS: 32%
  53. 53. TBF Single UCBT vs other MAC single UCBT vs TBI+CY+Flu double UCBT What are the results ?
  54. 54. p=0.03 Group 1: sUCBT-CyTBI12: 30±7%, n=68 (Cell dose 2.9) Group 2: sUCBT-BuFluTT+ATG: 46±6%, n=88 (Cell dose 3.1) Group 3: dUCBT-CyFluTBI12: 48±6%, n=83 (Cell dose 3.7) LFS at 2 years MAC sUCBT and dUCBT in adults with AL in CR1
  55. 55. Which is the “best” RIC for UCBT?
  56. 56. Disease Free Survival according to conditioning after single and double UCBT for malignancies in adults ( n=155) Months 28% others 51% CY+TBI 2GY+FLU (n=101) P= 0.0002
  57. 57. 0 10 20 30 0.00.20.40.60.81.0 Months Probability Relapse 2 year estimate: 46% Phase II trial in France on the use of TCF–RIC in UCBT for AML ( n=79) Cumulative Incidence of Relapse Rio B et al Should we include Thiotepa or increase TBI in the RIC ?
  58. 58. UCBT for adults with Malignancies • Eurocord Registry update • Indications • Survey on outcomes for specific diseases • Survey on outcomes of elderly patients in Europe and USA • Conditioning regimen • Complications (engraftment)
  59. 59. PROBABILITY OF ENGRAFTMENT • The Probability Density to engraft describes the probability to engraft at each time point from CBT, also considering competing events (ie early deaths) • The engraftment probability peaks at +21, the median halves at +31 (20%) and drops to 5% at day 42 -0.0050 0.0000 0.0050 0.0100 0.0150 0.0200 0.0250 0.0300 0.0350 0.0400 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 20% 5% The area under the curve beyond each time points represents the residual probability to engraft
  60. 60. Conclusions Single and unrelated cord blood with myeloablative or reduced intensity conditioning regimens are feasible procedures and have extented the use of allo transplants for patients without a HLA matched donor Graft failure and delayed neutrophil recovery are still problems to be circumvent in the field of UCBT Analysis of risk factors in specific diseases are important with the aim to improve final outcomes.
  61. 61. Leukemia-free Survival after Single UCBT – MAC in adults with leukemias - Transplantation in Remission - Probability,% 100 0 20 40 60 80 90 10 30 50 70 Months 0 6 12 18 24 8/8 matched BM 246 177 139 99 82 7/8 matched BM 106 69 46 35 31 8/8 matched PBPC 452 316 220 143 112 7/8 matched PBPC 166 89 66 45 36 4/6-6/6 matched UCB 123 77 47 30 24 8/8 BM, 52% 7/8 BM, 41% 8/8 PBPC, 50% PBPC 39% 4-6/6 UCB, 44% Eapen et al; Lancet Oncol 2010
  62. 62. 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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