Cord Blood Transplantation Clinical and patient perspectives

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Cord Blood Transplantation Clinical
and patient perspectives

• Naynesh R. Kamani, M.D.,
• Childrens National Medical Center
• GW University School of Medicine

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Hematopoietic stem cell transplantationSources
of stem cells

• 1960s -1980s related donor bone marrow
• 1980s- unrelated donor bone marrow
• 1980s- peripheral blood stem cells
• 1988- related donor cord blood
• 1990s unrelated donor cord blood

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Hematopoietic stem cell transplantation Why
the need for alternative stem cell sources?

• Only 25-30 of eligible HSCT candidates have
  HLA-identical related donors
• Despite registries listing 5 million volunteer
  BM/PBSC donors, well matched unrelated donors
  cannot be identified for upto 20-25 of eligible
  patients (significantly higher for minority
  patients)

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Cord blood transplantationHistorical review

• Early 1980s Preclinical work to establish CB
  as a source of hematopoietic stem cells
• 1988 1st successful matched sib CBT for FA
• 1992 Establishment of allogeneic CB banks
• 1993 1st successful URD CBT reported
• 1996 1st successful CBT reported in adult
• 1993- 2500 CBTs performed, mostly URD and
  mostly in children

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First matched sib CBT

• 5 yr-old boy with Fanconis anemia transplanted
  with umbilical cord blood from unaffected
  HLA-identical sister.
• 0.4 x 108 nuc. cells/kg (cf. 1-5 x 108/kg BM)
• Slightly delayed hematopoietic recovery
• Long-term donor chimerism demonstrated
• Gluckman et al NEJM 3211174, 1989

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Cord blood transplantationHistorical review

• Early 1980s Preclinical work to establish CB
  as a source of hematopoietic stem cells
• 1988 1st successful matched sib CBT for FA
• 1992 Establishment of allogeneic CB banks
• 1993 1st successful URD CBT reported
• 1996 1st successful CBT reported in adult
• 1993- 2500 CBTs performed, mostly URD and
  mostly in children

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ALLOGENEIC STEM CELL SOURCESBY RECIPIENT
AGE 1996-2002
100
Bone Marrow Peripheral Blood Cord Blood
80
60
OF TRANSPLANTS
40
20
0
1996-1998
1999-2002
1996-1998
1999-2002
Age 20 yrs
Age 20 yrs
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ALLOGENEIC TRANSPLANTS IN PATIENTS 20 yrs
REGISTERED WITH IBMTR, 1989-2003 - By Donor Type
-
5,000
Related Unrelated
4,000
3,000
TRANSPLANTS
2,000
1,000
0
1989-1990
1991-1992
1993-1994
1995-1996
2001-2002
1999-2000
1997-1998
Data incomplete
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ALLOGENEIC TRANSPLANTS IN PATIENTS 20 yrs
REGISTERED WITH IBMTR, 1989-2002 - By Donor
Type -
12,000
Related Unrelated
10,000
8,000
6,000
TRANSPLANTS
4,000
2,000
0
1989-1990
1991-1992
1993-1994
1995-1996
2001-2002
1999-2000
1997-1998
Data incomplete
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HSCT - Indications

• Malignant diseases of bone marrow
• e.g. ALL, AML, JCML, CML, MDS, lymphomas
• Marrow failure states
• e.g. severe aplastic anemia, Fanconi anemia
• Diseases where hematopoietic stem cell derived
  cells can provide deficient enzymes
• e.g. Hurler syndrome, adrenoleukodystrophy,
  metachromatic leukodystrophy

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HSCT - Indications

• Inherited lympho-hematopoietic disorders
• Lymphoid SCID, WAS, X-HIgM
• Myeloid CGD, LAD, Kostmanns
• erythroid Sickle Cell Disease, thalassemia
• monocyte/macrophage osteopetrosis
• platelets WAS

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CORD (PLACENTAL) BLOODAdvantages

• Abundantly available source of stem cells
• Ethnic balance can be maintained
• Infectious agents (e.g.CMV/EBV) less likely
• Shortened time from search to transplant

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Maintaining ethnic balance

• COBLT NMDP
• (n1794) (3.48x106)
• White 50.3 57.2
• AA 15.1 7.8
• Hispanic 15.6 7.6
• Asian 7.0 5.8
• Mix/other 12.0 21.5

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UMBILICAL CORD (PLACENTAL) BLOOD Advantages

• Long shelf life making UCBT logistically
  simpler
• Repository can be manipulated as needed
• Attrition of units doesnt occur
• Absence of risk to mother/donors
• Potential reduced risk of GVHD thus allowing
  less stringent match criteria

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Matched unrelated donor BMT

• A11,B55,C9,DR1401,DQ02AB A11,B55,C9,DR1401,DQ02AB
  A1, B8,C7, DR0301, DQ0503 A1, B8,C7, DR0301,
  DQ0503 recipient donor
• A0201,B4101,C17MN,DR1104,DQ03AK A0201,B4101,C17MN,
  DR1104,DQ03AK
• A0301, B0702,C0702, DR1501, DQ0602 A0301,
  B0702,C0702, DR1501, DQ0602
• recipient donor

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Unrelated Cord Blood Transplant

• A2,B7,DR0402 A2,B7,DR0402
• A3,B78,DR302 A3,B78,DR0302
• recipient donor
• A2,B7,DR0401 A2,B7,DR0402
• A3,B78,DR0302
  A3,B78,DR0302
• recipient donor

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Unrelated Cord Blood Transplant

• A2,B7,DR0402 A2,B7,DR0402
• A3,B65,DR0302
  A3,B78,DR0302
• recipient donor
• A74,B53,DR0301 A2,B38,DR0301
• A26,B65,DR1302 A26,B65,DR1302
• recipient donor

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UMBILICAL CORD (PLACENTAL) BLOODDisadvantages

• Risk of transmitting undiagnosed genetic
  diseases
• HSC numbers vary greatly with no chance for
  recollection
• Insufficient HSC for large patients
• Significant risk of non-engraftment/delay in
  hematopoietic engraftment
• Risk of maternal blood contamination

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RESULTS OF CBTSummary

• No randomized trials comparing BM vs CB
• Risk of GVHD less compared to unrelated donor BMT
  allowing less stringent matching criteria
• Delay in hematopoietic engraftment and increased
  risk of graft failure
• Matched cohort studies have shown that LFS is
  comparable between matched unrelated donor BMT
  recipients and matched or mismatched unrelated CB
  recipients
• Can be an alternative source of stem cells

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Procedure for unrelated cord blood donor searches

• Search initiated through NMDP
• Essentially all potential adult donors identified
• Potential CB matches (listed with NMDP)
  identified
• Concurrent searches initiated through NYBC and
  several other smaller domestic CB banks
  (individual searches)
• Additional searches of foreign CB banks

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Choosing between marrow/CB donors

• Availability of donors (likelihood of match)
• Degree of matching
• Indication - underlying disease
• Urgency of transplant e.g. refractory AML, SCID
• For CB units
• degree of match (3-6/6)
• size of recipient vs. number of cells (NC vs
  CD34 cells)

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Indication as a determining factor

• Severe combined immune deficiency
• urgency of transplant is critical
• requirement for low cell dose
• less risk of graft vs host disease
• lower risk of infectious disease transmission
• ALL in 2nd remission
• urgency of transplant not critical
• graft vs host disease may be beneficial

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Future Directions

• Streamlining the search process to simplify and
  accelerate the process for identifying available
  unrelated CB units
• Increasing inventory of unrelated CB units with
  emphasis on minority CB recruitment
• Standardization of processes for
  collection/processing, cryopreservation, storage,
  thawing of CB units
• Research on CB as a continuing source of stem
  cells

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Research questions

• Better definition of matching criteria through
  analysis of current and future data
• Better definition of cell dose requirements
  necessary for engraftment
• Increased use of CB as a stem cell source for
  large recipients
• use of multiple CB units
• use of in-vitro expanded CB units

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Research questions

• Graft vs leukemia potential of CB
• Role of CBT in non-myeloablative or reduced
  intensity transplants
• Gene therapy utilizing CB cells as targets

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• Thank you for your attention