Cord Blood Transplantation Single or Double Cord ???

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Cord Blood TransplantationSingle or Double Cord
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• Diana Worthington-White
• Cellular Therapies Lab

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Laboratory Processing as aScientific Discipline

• Began in mid 1980s
• 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

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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

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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)

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An Alternative Cell Source

• CORD BLOOD
• Readily available
• Routinely discarded at childbirth
• Harvest the cord blood and freeze it for
  transplant

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Collecting the Cord
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Collecting the Cord
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First Cord Blood Transplant

• 1988
• Child with Fanconis anemia complicated by severe
  aplastic anemia
• During pregnancy, mother carried sibling
  unaffected by disease and HLA identical
• Cord collected and frozen in liquid nitrogen

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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)

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Cord Blood A New Source

• Advantages
• Worldwide availability
• Cells not fully immunogenic ? less HLA matching
  required
• Increase donor pool
• Minorities
• Diversity

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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

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Big Things Come in Small Packages
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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

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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

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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

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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

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Limitations of Cord Blood Transplants in Adults

• Important factors
• HLA-mismatch (gt 2) ? transplant-related
  mortality
• Cell dose lt 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

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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

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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

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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

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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

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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

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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

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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

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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

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

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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)

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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

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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)

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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

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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

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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

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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

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Private Cord Blood Banking
VidaCord
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American Academy of Pediatrics

• Estimates that the chance of a child needing
  their own stored cord blood range from 11000 to
  1200,000
• 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
  infants cord blood
• Cord blood banking for public use should be
  encouraged
• Private storage of cord blood as biological
  insurance should be discouraged

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Stem Cell Act of 2005

• 78 million dollars earmarked to expand the
  number of public cord blood units banked in the US

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Single or Double???

• Depends on
• Weight
• Disease
• Availability of cord blood unit
• Size of the cord blood unit