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Federico Garnier - France - Tuesday 29 - Hematopoietic Stem Cells

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Federico Garnier - France - Tuesday 29 - Hematopoietic Stem Cells

  1. 1. UMBILICAL CORD BLOOD TRANSPLANTATION Dr Federico GARNIER Associate Director Bone Marrow Donor Registry France Greffe de Moelle
  2. 2. UMBILICAL CORD BLOOD TRANSPLANTATION Conflict of Interest/Financial Disclosure The Speaker voluntarily disclosed the following pertinent financial relationships and/or conflicts of interest: I have NO conflicts of interest
  3. 3. Sources of Haematopoietic Stem cells CSH Bone Marrow Umbilical cord blood Peripheral blood
  4. 4. Estimated probability of finding a donor in candidates for HSCT Candidates for cord blood or haplo SCT
  5. 6. HEMATOPOIETIC RECONSTITUTION IN A PATIENT WITH FANCONI’S ANEMIA BY MEANS OF UMBILICAL-CORD BLOOD FROM AN HLA-IDENTICAL SIBLING Gluckman E, Broxmeyer HA, Auerbach A et al. New England J Med 1989;321:1174-78 A single unit of Umbilical Cord Blood contained enough haematopoietic stem cells to reconstitute definitely the host lympho-haematopoitic compartment
  6. 7. The use of UCB units <ul><li>ADVANTAGES </li></ul><ul><li>Faster availability of banked cryopreserved CBU </li></ul><ul><li>Tolerance to 1-2 HLA mismatches </li></ul><ul><li>Lower incidence and severity of GVHD </li></ul><ul><li>Lower risk of transmitting infections (CMV, EBV) </li></ul><ul><li>Lack of risk to the donor </li></ul><ul><li>Higher frequency of rare haplotypes </li></ul><ul><li>LIMITS </li></ul><ul><li>Low number of cell dose </li></ul><ul><li>(NC and CD 34 + ) </li></ul><ul><li>Increased risk of graft failure </li></ul><ul><li>Delayed hematopoietic engraftment </li></ul><ul><li>Delayed immune reconstitution </li></ul><ul><li>2 nd donation is not possible </li></ul>
  7. 8. Related Cord Blood Transplants n=78 ANC recovery according to NC and HLA matching days 0 ,1 ,2 ,3 ,4 ,5 ,6 ,7 ,8 ,9 1 0 10 20 30 40 50 60 HLA match HLA mismatch p = 0.04 0 ,1 ,2 ,3 ,4 ,5 ,6 ,7 ,8 ,9 1 0 10 20 30 40 50 60 > 3.7 x10 7 /kg < 3.7 x10 7 /kg p = 0.05 days Gluckman E, et al, NEJM 1997
  8. 9. Unrelated Cord Blood Transplants n=65 Gluckman E, et al, NEJM 1997 ANC recovery according to NC and HLA matching days 0 ,1 ,2 ,3 ,4 ,5 ,6 ,7 ,8 ,9 1 0 10 20 30 40 50 60 > 3.7x10 7 /kg < 3.7x10 7 /kg p = 0.008 days 0 ,1 ,2 ,3 ,4 ,5 ,6 ,7 ,8 ,9 1 0 10 20 30 40 50 60 HLA match HLA mismatch p = 0.03
  9. 13. Unrelated Cord Blood versus allele typing Unrelated Bone Marrow Transplants in Children with Acute Leukemia M Eapen et al on behalf of CIBMTR and NYBC
  10. 14. UCBT versus allele typing UBMT Disease Characteristics <ul><li>BM CB </li></ul><ul><li>(n=282) (n=503) </li></ul><ul><li>Disease ALL 69% 61% AML 31% 39% </li></ul><ul><li>Disease status * 1 st CR 17% 21%  2 nd CR 67% 50% Relapse/PIF 16% 29% </li></ul>* P < 0.05 Eapen M et al Lancet. 2007, 369:1947-54
  11. 15. Neutrophil Recovery Days 0 20 40 100 Probability, % 100 0 20 40 60 80 80 60 BM (n=116), 97% CB matched (n=35), 85% CB MM high dose >3.5 (n=362), 79% CB MM low dose<3.5 (n=97), 64%
  12. 16. Leukemia-free Survival Adjusted Probability, % 12 24 60 48 36 0 Months CB matched (n=35) 60% CB 1-Ag MM >3.5x10 7 /kg (n=157) 45% BM matched (n=116) 38% CB 2-Ag MM (n=267) 33% CB 1-Ag MM <3.5x107/kg (n=44) 35% Eapen M et al Lancet. 2007, 369:1947-54 0 20 40 60 80 100
  13. 17. Comparative studies between UCBT and UBMT in adults ENGRAFTMENT ACUTE GVHD CHRONIC GVHD EARLY TRM RELAPSE SURVIVAL Rocha NEJM 2004; Laughlin NEJM 2004; SANZ Blood 2004; Takahashi Blood 2004 Cord blood vs Bone Marrow
  14. 18. Enhancing engraftment <ul><li>Co-infusion of 2 partially HLA matched CBU (Barker et al, 2005; Brunstein et al 2007) </li></ul><ul><li>Use of reduced intensity conditioning (Barker et al, 2003; Brunstein et al 2007; Ballen et al 2007; Rocha et al 2009) </li></ul><ul><li>Ex vivo CB expansion (E Shpall et al, 2002; de Lima et al,2008) </li></ul><ul><li>Transplantation of ex vivo expanded cord blood cells </li></ul><ul><li>On-going: Notch-mediated ex vivo expansion of CD34+ CB progenitors: C Delaney et al 2011 </li></ul><ul><li>Third party donor co infusion (M Fernandez et al, 2003; Magro et al, 2006) </li></ul><ul><li>Early hematopoietic recovery after single unit unrelated cord blood transplantation in adults supported by co infusion of mobilized stem cells from a third party donor. </li></ul><ul><li>Intra-bone injection (Frassoni et al, 2008) </li></ul><ul><li>Direct intrabone transplant of unrelated cord-blood cells in acute leukaemia: a phase I/II study . </li></ul><ul><li>Enhacing HSC homing Christopherson KW II, et al. Stem Cells Dev 2007 </li></ul><ul><li>Use of CD26 inhibition on CD34+or lineage-human umbilical cord blood donor hematopoietic </li></ul><ul><li>stem cells/hematopoietic progenitor cells </li></ul><ul><li>Mesenchymal stem cell Co infusion (Macmillan et al, 2009) </li></ul>
  15. 19. Co infusion of 2 Cord blood units Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancies . Barker et al. Blood 2005 ; 105:1343-1347
  16. 24. Comparative Retrospective Registry Based Analysis <ul><li>Selection criteria </li></ul><ul><li>First single (n=378) or double (n=213) cord blood transplants performed from 2000 to 2008 </li></ul><ul><li>Adults ≥ 18 years with AML or ALL in complete remission </li></ul><ul><li>Myeloablative or reduced intensity conditioning regimen </li></ul>
  17. 25. sUCBT versus dUCBT for adults with AL Neutrophil recovery 60 50 40 30 20 10 0 1,0 ,8 ,6 ,4 ,2 0,0 87 ± 2% 86 ± 2% dUCBT sUCBT
  18. 26. sUCBT versus dUCBT for adults with AL 100 day CI of Acute GVHD II-IV days 25 ± 2% 36 ± 3% P=0.004 dUCBT sUCBT
  19. 27. 26 ± 2% 18 ± 3% P=0.06 months sUCBT versus dUCBT for adults with AL 2 years Relapse incidence dUCBT sUCBT
  20. 28. 36 ± 3% 37 ± 4% P=0.62 months sUCBT versus dUCBT for adults with AL 2 y CI of non-relapse mortality dUCBT sUCBT
  21. 29. 38 ± 3% 45 ± 3% P=0.05 months sUCBT versus dUCBT for adults with AL 2 y LFS dUCBT sUCBT
  22. 30. Multivariate models adjusted for differences between two groups <ul><li>Acute GVHD II-IV </li></ul><ul><li>dUCBT HR=1.20; 95%CI=1.05-1.37; p=0.007 </li></ul><ul><li>Chronic GVHD </li></ul><ul><li>dUCBT HR=1.02; 95%CI=0.89-1.20; p=0.71 </li></ul><ul><li>Non relapse mortality </li></ul><ul><li>dUCBT HR=1.03; 95%CI=0.91-1.16; p=0.67 </li></ul><ul><li>Relapse </li></ul><ul><li>dUCBT HR= 0.76; 95%CI=0.64-0.91; p=0.002 </li></ul><ul><li>LFS </li></ul><ul><li>dUCBT HR=1.23; 95%CI=0.89-1.69-.; p=0.21 </li></ul>
  23. 33. Eurocord registry Data Base <ul><li>7868 cord blood transplantations performed from 1988 to December 2010 in 51 countries and 524 transplant centers*: </li></ul><ul><ul><ul><ul><li>278 EBMT 5734 (74%) cases </li></ul></ul></ul></ul><ul><ul><ul><ul><li>246 Non-EBMT 2049 (26%) cases </li></ul></ul></ul></ul>
  24. 34. Number of CBT by year reported to Eurocord Related n=596 Unrelated n=6140 Children n=3287 Adults n=2770 Unrelated CBT according to recipient age by year *Still collecting data * * Eurocord registry Data Base
  25. 35. Malignant n=4944 Non malignant n=1647 Eurocord registry Data Base
  26. 36. Double UR CBT/ year n=1080 *Still collecting data Reduced intensity Conditioning before UR CBT/year n=1516 * * Eurocord registry Data Base
  27. 37. Eurocord registry Data Base
  28. 38. <ul><li>Cell dose: > 3x10 7 NC/kg and/or > 1.0x10 5 CD34+/kg </li></ul><ul><li>in MAC, RIC , single and double UCB transplantation </li></ul><ul><li>Consider sensitization to HLA: patients should be tested for Ab directed against specific HLA antigens </li></ul><ul><li>HLA match (and ethnic ancestry, if possible) </li></ul><ul><ul><li>6/6 or 5/6 better than 4/6 avoid 3/6 and prefer class I MM than class II </li></ul></ul><ul><ul><li>In CBU 6/6 or 5/6, look at HLA C (select HLA C matched CBU) </li></ul></ul><ul><ul><li>If mother’s CBU HLA typing is available and many units exist, select NIMA </li></ul></ul><ul><ul><li>matched CBU </li></ul></ul><ul><li>Consider the indication </li></ul><ul><ul><li>Malignant diseases: cell dose is the best prognostic factor </li></ul></ul><ul><ul><li>because HLA differences reduce relapse (GVL) </li></ul></ul><ul><ul><li>Non malignant diseases: increase cell dose ( > 4.0x10 7 NC/kg ) </li></ul></ul><ul><ul><li>and find the best HLA match. </li></ul></ul><ul><li>Other factors </li></ul><ul><ul><li>It seems that in double CBT number of HLA disparities and ABO </li></ul></ul><ul><ul><li>compatibility is also important </li></ul></ul><ul><ul><li>Consider KIR only in the context of clinical trial </li></ul></ul>Guidelines for cord blood selection
  29. 39. Conclusions <ul><li>Cell dose is the major factor for outcomes in children and adults, after either myelo-ablative or reduced preparative schemas. </li></ul><ul><li>Outcomes after UCBT, mainly in adults, have been improved in the recent years: still on the learning curve and follow-up is short. </li></ul><ul><li>Delayed engraftment and early increased mortality are associated with higher number of HLA disparities: need to increase the donor pool. </li></ul><ul><li>Other modifiable factors such as conditioning regimen and GVHD prophylaxis can improve outcomes. </li></ul><ul><li>Encouraging results with double cord blood after RIC or MAC, but still short follow-up. </li></ul>
  30. 40. Thank you

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