Cord Blood Transplantation Single or Double Cord ???

1. Cord Blood TransplantationSingle or Double Cord ??? Diana Worthington-White Cellular Therapies Lab

2. Laboratory Processing as aScientific Discipline • Began in mid 1980’s • Remove tumor cells from autologous bone marrow • Management of blood type incompatibilities • Washing • Red cell depletion • Results • Increased number of eligible patients • Increased number of diseases that could benefit from transplant

3. Processing Expands • Only 30% of patients have an HLA-match • Could use less-matched donors if certain cell types (T-cells) could be reduced • Laboratory developed methods to selectively deplete most T-cells while retaining stem cells • Processing labs now called graft engineering labs

4. Donors, donors, donors • Patients that could benefit from a transplant based on disease status still could not receive one • Why not → Lack of donors • Alternative sources • Unrelated registries (e.g., National Marrow Donor Program)

5. An Alternative Cell Source CORD BLOOD • Readily available • Routinely discarded at childbirth • Harvest the cord blood and freeze it for transplant

6. Collecting the Cord

7. Collecting the Cord

8. First Cord Blood Transplant • 1988 • Child with Fanconi’s anemia complicated by severe aplastic anemia • During pregnancy, mother carried sibling unaffected by disease and HLA identical • Cord collected and frozen in liquid nitrogen

9. First Cord Blood Transplant • Patient received chemotherapy and radiation • Cells were then thawed and infused • No immediate side effects • Complete hematologic reconstitution • No chronic graft-versus-host disease (GVHD)

10. Cord Blood – A New Source Advantages • Worldwide availability • Cells not fully immunogenic → less HLA matching required • Increase donor pool • Minorities • Diversity

11. Standardization • Patient Selection • Since cells less immunogenic, how much of a mismatch could be tolerated (1 vs. 2 vs. 3) • Collection • Kits now available for collection • Maternal testing reduced units discarded for infectious disease positivity, family history • Processing • Cord blood cells fragile • Less is better

12. Big Things Come in Small Packages

13. Published Reports Pediatric patients • High probability of survival when • ≤ 2 HLA antigen mismatch • CD34 dose ≥ 1.7x105/kg recipient weight • Neutrophil engraftment significantly slower but catches up by day +45 • Low incidence of severe acute or chronic GVHD • Comparable to HLA-mismatched bone marrow transplantation Barker et al, Blood, 2001 Wagner et al., Blood, 2002

14. Published Reports Pediatric patients • Compared matched unrelated donor bone marrow to cord blood • Takes 29 more days to identify and clear a donor for an unrelated bone marrow than for cord blood • Faster availability is an advantage for patients requiring urgent transplantation Barker et al., Biol Blood Marrow Transpl, 2002

15. Published Reports Adult patients • Compared cord blood with mismatched unrelated donor bone marrow • Mismatched unrelated bone marrow and mismatched cord blood comparable in terms of graft failure and overall mortality • No difference between 1 or 2 antigen mismatch for cord blood • Chronic GVHD more common after cord blood transplant Patients tended to be younger and more likely to have advanced leukemia (dose consideration) Laughlin et al., N Engl J Med, 2004

16. Early Conclusions Significant HLA mismatch is tolerable (4/6 or 5/6 cord blood comparable to 8/8 marrow) Graft-versus-host disease low despite the mismatch Graft-versus-leukemia effect increases with HLA mismatch Cell dose is critical for engraftment Cord Blood Transplant Study (COBLT), NHLBI, Prospective multicenter study Joint retrospective analysis by New York Blood Center and CIBMTR

17. Limitations of Cord Blood Transplants in Adults • Important factors • HLA-mismatch (> 2) = ↑ transplant-related mortality • Cell dose < 2.5x107/kg • Lower cell dose = delayed engraftment, increased graft failure • 4/6 match with larger dose better than 5/6 with smaller dose • Factors not important • Gender • Ethnicity • US/non-US cord blood center

18. Overcoming Dose Limitations • Clinically optimize peri-transplant therapy • Improve collection volumes • Ex vivo expansion of cord blood unit • Copper chelation • Hypomethylation • Mesenchymal stem cells (No demonstrable effect so far) • Infuse two partially-mismatched cord blood units

19. Double Cord Questions Are the doses additive? What about the mismatch between the units? Will both survive to give mixed chimerism? What about GVHD? GVHD directed against recipient GVHD directed against each cord blood unit

20. Published Study • Median age = 24 yrs • Both cord blood units given intravenously • Partially mismatched with recipient and between units • (≤ 2 antigen mismatch with each other and with recipient) • Median dose given = 3.5x107 cells/kg • Results: • All patients engrafted by day +23 • 24% had mixed chimerism at day +21 • 1 cord blood unit predominated in all patients at d +100 • Conclusion: • Transplant with two partially-HLA matched units safe and may overcome cell dose barrier Barker et al., Blood, 2005

21. Double Cord Transplants • Most important factor for engraftment • Total cell doses of both units combined • Factors not important • Disease status at transplant • Conditioning regimen • GVHD prophylaxis • HLA disparity • CD34+ dose • Gender • Age

22. Which cord unit “wins”? • Factors not important • Age • Gender • Order of infusion • CD34 or CD3 dose • ABO match • HLA disparity • Sex match Not known what determines the “winning” unit

23. Double Cord Transplants in Adults • 93% of adults now eligible for cord blood transplants (compared with 30% using a single unit if the threshold dose is 2.5x107/kg) • Engraftment is comparable to that in pediatric patients • Reduction in relapse rate of leukemia patients • Combined cell doses of both units most significant factor in predicting engraftment outcome • Higher rate of acute GVHD in younger patients

24. New Strategies • Extend double cord transplants using a non-myeloablative conditioning regimen to those not eligible for a myeloablative regimen • Early results indicate YES → dependent on amount of therapy in close time proximity to transplant • Transplant related mortality low in older patients • Enhancing the speed of engraftment • Intraosseous infusions

25. Transplant Infusions • Intravenous infusions inefficient – cells travel systemically until they reach the marrow space (homing) • Significant loss of cells en route to marrow • Overcome in bone marrow by infusion of large numbers of cells • Small numbers of cells from a cord blood infusion • Small volume and fixed dose • Cord blood homes less effectively

26. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intraosseous Infusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Can non-specific losses and homing to the BM microenvironment be optimized?

27. Current Studies • Infuse one unit intraosseously followed by the second (larger) unit infused intravenously • Few patients enrolled to date but all have engrafted quickly with no procedural side effects • Early indications are that the extra CD34+ cells in the second unit are important

28. Source of Cord Blood Units ARC Cord Blood Bank (Portland, OR) ARC/University of Minnesota Carolinas Cord Blood Center (Duke) LifeCord (Gainesville, FL) Michigan Community Blood Ctrs (Grand Rapids) New York Blood Center Puget Sound Blood Center (Seattle) St. Louis Cord Blood Center StemCyte (Arcadia, CA) Univ. Colorado Cord Blood Bank (Denver) Private cord blood banks (autologous/sibling)

29. International Cord Blood Banks Cord Blood Bank of Barcelona Cord Blood Bank of Leuven (Belgium) French Greffe de Moelle (Bordeaux) London Cord Blood Bank StemCyte Taiwan

30. Cost of Cord Blood Units Unrelated (public) • US: $18,540 to $33,641 • Foreign: $26,450 to $43,865 Private • $1199 – $2195 plus annual fee of $99 – $125 (range of 2007 fees for 10 private US cord banks)

31. Balancing Cost and Treatment • Significant difference in cost to procure cord blood unit(s) • Is cost balanced? • Earlier engraftment → earlier discharge • Less GVHD • Less risk of relapse • Only option for transplant

32. Need for Alternative Stem Cell Sources • The chance of finding a donor is: • 50% Caucasian • 35% Hispanic • 20% African American In 2003, 6% of all National Marrow Donor Program (NMDP) facilitated transplants used cord blood • In 2007, that number increased to 37%

33. Future of Unrelated Cord Blood Transplants • Cord blood has SURPASSED both bone marrow and peripheral stem cells as the primary stem cell transplant source in children in the U.S., Japan and several European countries • Cord blood has SURPASSED bone marrow and peripheral stem cells as the primary stem cell transplant source in adults in Japan and is growing rapidly worldwide

34. Cord Blood Banking • Expanding the use of cord blood will increase the interest in private cord blood banking • Arguments against private banking are: • Autologous cord blood may include stem cells predisposed to leukemia • The most common indication for transplant is acute lymphocytic leukemia • While this is true for young children, there is an increasing list of true and potential indications

35. Private Cord Blood Banking VidaCord

36. American Academy of Pediatrics Estimates that the chance of a child needing their own stored cord blood range from 1:1000 to 1:200,000 Recommendations • Cord blood donation should be discouraged when cord blood is to be directed for later personal or family use, as most conditions that might be helped by cord blood already exist in the infant’s cord blood • Cord blood banking for public use should be encouraged • Private storage of cord blood as “biological insurance” should be discouraged

37. Stem Cell Act of 2005 $78 million dollars earmarked to expand the number of public cord blood units banked in the US

38. Single or Double??? • Depends on • Weight • Disease • Availability of cord blood unit • Size of the cord blood unit