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1989 First Cord blood transplant

Past and Present of Cord Blood Transplants. 1989 First Cord blood transplant 1989-92 Clinical observation that GVHD was reduced in HLA incompatible CBT 1992-93 Establishment of Cord blood banks (NY, Paris, Milan and Dusseldorf )

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1989 First Cord blood transplant

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  1. Past and Present of Cord Blood Transplants 1989 First Cord blood transplant 1989-92Clinical observation that GVHD was reduced in HLA incompatible CBT 1992-93 Establishment of Cord blood banks (NY, Paris, Milan and Dusseldorf ) 1993-95 Feasibility of HLA incompatible unrelated cord blood transplants 1995 Establishment of Eurocord group 1997 Nucleated cell dose more important factor for engraftment and survival , influence of HLA on engraftment 1998 Large series of UCBT = confirmation of cell dose and HLA >2000Retrospective comparisons between UBMT and UCBT 2002 Use of cord blood cells in adults with promising results 2003 Criteria of cord blood choice and indications 2003-04 Use of double cord and RIC regimen in adults 2004 Isolation of USSC from umbilical cord blood 2004-05 Comparable results between unrelated CBT and UBMT in adults

  2. NETCORD-EUROCORD INTERACTIONS NETCORD EUROCORD Standards Quality Control Accreditation FACT-Netcord Donor search Registry Protocols Clinical Studies CORD BLOOD BANKS TRANSPLANT CENTERS(EBMT and non EBMT) BMDW MUD Registries

  3. EUROCORD Registry 2842 cord blood transplantation performed from 1988 to Sep 2006 in 39 countries and 318 transplant centers: - 138 EBMT 1700 cases - 180 Non-EBMT 742 cases • Single CB transplant n=2680 Related n= 267 Unrelated n = 2313 • Expanded Unit n= 52 • Unit for multi cord n= 150 • UCB + BM (haplo) n= 14 • CB + BM (genoidentical) n= 18 • Autologous or gene therapy n=4

  4. CLINICAL RESULTS Related Cord Blood Transplantation

  5. Related Cord Blood Transplantation (n=231) Survival according to diagnosis 1,0 ,9 ,8 ,7 ,6 ,5 ,4 ,3 ,2 ,1 ,0 0 12 24 48 60 36 Hbpathies n=63 100% 83 8% Inborn Errors n=23 Bone marrow failures n=37 78 7 % Malignancies n=109 47 5% months

  6. 5 years EFS according to diagnosis 1,0 Sickle cell disease (n=19) 94%+6 ,9 ,8 Thalassemia (n=44) 78%+6 ,7 ,6 ,5 ,4 ,3 ,2 ,1 Months 0,0 0 6 12 18 24 30 36 42 48 54 60

  7. 1,0 7112% Early phase n=14 ,8 457% ,6 Intermediate phase n=49 ,4 247% Advanced phase n=35 ,2 0,0 months 0 24 48 72 Related cord blood transplantation for maligancies (n=109) Survival according to status of the disease at CBT

  8. COMPARISON OF GVHD AFTERHLA-IDENTICAL SIBLING CORD BLOOD vs BONE MARROW TRANSPLANTS IN CHILDREN International Bone Marrow Transplant Registry and Eurocord V Rocha et al NEJM 342: 1846-1854, 2000

  9. MULTIVARIATE ANALYSIS- GVHD - 1.2 * * 1.0 BM n=2018 CB n=113 0.8 RELATIVE RISK 0.6 .001 0.4 .02 0.2 0.0 Grade II-IVAcute GVHD ChronicGVHD * Reference Group GVH98_19.ppt

  10. MULTIVARIATE ANALYSIS- Hematopoietic Recovery & Survival - 1.2 NS BM CB * * * * NS 1.0 0.8 RELATIVE RISK 0.6 .0001 0.4 .0001 0.2 0.0 Early Late Platelets >20 x 109/L ANC >0.5 x 109/L Mortality * Reference Group GVH98_25.ppt

  11. 100 80 60 40 20 0 Survie Globale après greffes HLA identiques de SCO comparées aux greffes de MO chez les enfants selon les diagnostiques Non malignes, SCO (N = 52) Non-malignes, MO (N = 789) Malignes, MO (N = 1,263) PROBABILITE DE SURVIE, % Malignes, SCO (N = 61) 0 1 2 3 4 5 ANNEES V Rocha, J Wagner, K Sobosinski et al, NEJM 342: 1846-1854, 2000

  12. Indications of cord blood banking for family use • Sibling with a disease which can be cured by hematopoietic stem cell transplantation: Poor risk leukemia, aplastic anemia, hereditary disorders. • HLA mismatched transplants with 1, 2 or full haplotype (?) • Familial predisposition to malignancies • Genetic disease (autologous use for gene therapy)

  13. Unrelated Cord Blood Transplantation

  14. Estimate number of patients with an indication of an allogeneic hematopoietic stem cell transplants (9 or 10 out of 10)

  15. Advantages and disadvantages Searching and identifying an unrelated stem cell donor BM CB Information of A+B (serology) +DRB1(DNA) typed 16-56% 40-80% Median search time 3-6 mon <1mon Donors identified but not available 30% ~1(?)% Rare Haplotypes represented 2-10% 20% Major limiting factors to graft acquisition HLA match Cell Dose Ease of rearranging date of cell infusion Difficult Easy Potential for second HSC graft or DLI Yes No from the same donor Potential for viral transmission to recipient Yes No congenital diseases No Yes Risk to donor Yes No Grewal S et al, modified Blood 2003

  16. UNRELATED TRANSPLANTS BY RECIPIENT AGE- Registered with CIBMTR, 1996 to 2003 - 100 90% Bone Marrow Peripheral Blood Cord Blood 80 72% 56% 60 50% TRANSPLANTS, % 39% 36% 40 25% 14% 20 6% 5% 4% 3% 0 1996-1999 2000-2003 1996-1999 2000-2003 Age < 20 yrs Age > 20 yrs CBT04_11.ppt

  17. Number of Unrelated CBT / year reported to Eurocord Unrelated n=2172 *Still collecting data 2005

  18. Number of Unrelated Donor CBT according to the recipient age/year reported to Eurocord Children (1320) Adults (693) * 2005

  19. EUROCORD UNRELATED CORD BLOOD TRANSPLANT IN CHILDREN Eurocord Registry

  20. 1,0 ,9 ,8 ,7 CR1 n=28: 57%+10 ,6 ,5 CR2 n=79: 47%+6 ,4 ,3 ,2 other n=47: 22%+7 P <.0001 ,1 ,0 Months 12 24 36 48 60 UCBT in children with AML (n=154) Leukemia free survival according to the status of the disease at transplant G Michel updated , Blood 2003

  21. Outcome after Unrelated Umbilical Cord Blood Transplants for Children with Acute Lymphoblastic Leukemia V Rocha, M Labopin, G Michel, N Kabbara, W Arcese, J Ortega, A P Iori, L Madero K-W Chan, F Locatelli, F Garnier, I Ionescu, P Wernet, E Gluckman Eurocord and Acute Leukemia Working Party of EBMT Hôpital Saint-Louis, Paris

  22. Patient and disease characteristics (n=361) CR1 87 4.7 (0.4-16) 18% 43% 0 - CR2 152 6.7 (0.7-16) <1% 44% 2% 21 mo Advanced 122 8.0 (0.5-16) <1% 58% 10% 23 mo N Median age at UCBT < 1 year +CMV Recipient Previous autograft Duration of first CR

  23. Disease Characteristics Advanced (n=122) 66% 12% 14% 6% 2% 39% CR2 (n=152) 56% 19% 16% 3% 6% 38% CR1 (n= 87) 47% 21% 17% 7% 8% 89% Pre-B B T Null Biphenotypic Poor risk Cytogenetics t (9;22), t (4;11)

  24. Outcomes after UCBT for children with ALL (n=361)

  25. 1.0 >5.7 88% 3.8-5.7 81% 2.6-3.8 73% 0.8 < 2.6 63% 0.6 0.4 P (gray test) <0.001 0.2 0.0 days 0 10 20 30 40 50 60 UCBT for Children with ALL Cumulative incidence of neutrophil recovery according to number of cells infused (107/kg) (per quartiles) (n=361)

  26. Leukemia Free Survival according to disease status (n=361) 1.0 .8 .6 CR2 35 ± 4% .4 CR1 33 ± 7% .2 Adv 21 ± 4% P (log rank test) <0.001 0.0 0 10 20 30 40 50 60 months UCBT for Children with ALL

  27. Risk factors of outcomes after UCBT for children with ALL in 2nd CR (n=152)

  28. UCBT for Children with ALL in CR2 (n=152) Relapse incidence according to previous relapse on or off chemotherapy 1.0 0.8 0.6 on therapy n=73 39 ± 4% 0.4 off therapy n=65 14 ± 7% 0.2 P (gray test) =0.001 0.0 months 0 10 20 30 40 50 60

  29. UCBT for Children with ALL in CR2 (n=152) 1.0 Leukemia free survival according to first relapse on or off chemotherapy .8 .6 off therapy n=65 45 ± 7% .4 on therapy n=73 26 ± 6% .2 P (log ranktest) <0.001 0.0 0 10 20 30 40 50 60 months

  30. Results of multivariate analysis in CR2 patients

  31. UCBT for Children with ALL in CR2 (n=152) Causes of death (n=86)

  32. Comparative studies between UCBT and UBMT in children (V Rocha Blood 2001, J Barker Blood 2001, H Dalle BMT 2004, Jacobson BMT 2004, P Rubinstein ASH 2005) Cord blood vs Bone Marrow ENGRAFTMENT ACUTE GVHD CHRONIC GVHD EARLY TRM RELAPSE SURVIVAL

  33. Non malignant diseases in children

  34. Overall survival after UCBT in patients with bone marrow failure syndromes 1,0 Congenital aplastic anemia n=16 63% ,8 ,6 Fanconi anemia n= 92 34% ,4 Severe aplastic anemia n= 19 21% ,2 0,0 0 3 6 9 12 15 18 21 24 27 30 33 36

  35. 1,0 ,8 6/6 (n=13) 76% + 12 ,6 5/6 (n=33) 37% + 9 ,4 3 or 4/6 (n=43) 18% + 6 ,2 p=0.009 0,0 Months 0 6 12 18 24 30 36 Survival after UCBT for Fanconi anemia (n=92) according to number of HLA differences (A, B antigen and DRB1 allelic)

  36. 1,0 ,9 ,8 ,7 ,6 Inborn errors n=65 61±7% ,5 ,4 ,3 ,2 ,1 months 0,0 0 6 12 18 24 30 36 42 48 Overall survival after UCBT in children with metabolic disorders

  37. Overall survival of children with Primary Immunodeficiencies according to Number of HLA differences (n=93) 1.0 78% HLA Identical or one difference out of 6 0.8 0.6 P(Survival) 58% 2 or 3 HLA differences out of 6 0.4 0.2 0.0 0 500 1000 1500 2000 2500 3000 Days

  38. EUROCORD UNRELATED CORD BLOOD TRANSPLANT IN ADULTS Results Eurocord Registry

  39. Overall Survival after UCBT for adults with hematologic malignancies n= 457 1,0 ,8 ,6 after 1998 35±3% (n=413) ,4 before 1998 18±6% (n=44) ,2 P <0.0001 0,0 0 6 12 18 24 30 36 42 48 54 60

  40. Leukemia Free Survival after UCBT fr adults with AML according to the disease status (n=87) 1,0 ,8 CR1 n=23: 60%+13 ,6 CR2 n=17: 51%+15 ,4 Others n=47: 15%+5 ,2 0,0 0 6 12 18 24 30 36

  41. 1,0 ,8 ,6 CR2 n=26: 42%+10 ,4 CR1 n=39: 31%+8 ,2 Others n=48: 18%+6 0,0 0 6 12 18 24 30 36 Leukemia Free Survival after UCBT for adults with ALL according to the disease status (n=113)

  42. EUROCORD Outcomes of Unrelated Cord Blood Transplants compared to Unrelated Bone Marrow Transplants in Adults with Acute Leukemia Aretrospective based registry study V Rocha on behalf of Eurocord and Acute Leukemia Working Party-EBMT New England Journal of Medecine , Nov 2004

  43. UCBT versus UBMT in adults with acute leukemias 1.0 Leukemia Free survival .8 .6 35 %  2 .4 32 %  6 .2 P (log rank)= 0.09 0.0 years 0 1 2

  44. MULTIVARIATE ANALYSIS- Hematopoietic Recovery & GVHD - UBMT UCBT 1.2 P=0.01 P=0.17 * * * * 1.0 P>0.0014 P<0.0001 0.8 RELATIVE RISK 0.6 0.4 0.2 0.0 Platelets >50 x 109/L Acute GVHD Chronic GVHD ANC >0.5 x 109/L * Reference Group

  45. MULTIVARIATE ANALYSIS- TRM , RELAPSE AND LFS - UBMT UCBT 1.2 P=0.29 P=0.46 * * 0.70 * 1.0 0.8 RELATIVE RISK 0.6 0.4 0.2 0.0 Relapse Leukemia Free Survival TRM * Reference Group

  46. Indication for allogeneic HSCT NO HLA identical sibling NO HLA matched unrelated donor Haplo Identical T-cell depleted PBSC Unrelated Cord Blood

  47. EUROCORD Comparison of outcomes after Unrelated Cord Blood or Haploidentical T-cell depleted Peripheral Blood Stem Cells in Adults with High Risk Acute Leukemia V Rocha, F Aversa, M Labopin, G Sanz, F Ciceri, W Arcese, D Bunjes, J Rowe, P Di Bartolomeo, F Frassoni, M Martelli and E Gluckman on behalf of the Eurocord-Netcord and Acute Leukemia Working Party EBMT

  48. Patients From 1998-2002 229 haplo and 139 UCBT were performed for adults with high risk acute leukemia (AML and ALL) Two different analysis were performed AML patients Haplo= 154 UCBT= 66 ALL patients Haplo= 75 UCBT= 73

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