2. Clinical Problem:
Allogeneic Graft Availability
Leukemia Patients Needing BMT
8/10 2/10
No Compatible Compatible Sibling
Family Donor Donor
Only 15-20% minority
patients receive BMT via
adult registry
3. Impact of Disease Stage and HLA
Matching on Unrelated HCT
Outcomes
Low Risk
Intermediate Risk
High Risk
4. Impact of Single HLA Mismatch
in Unrelated HCT for Low-risk
Disease
5. LFS after Cord Blood or Bone Marrow
Transplant from Unrelated Donors in
Adult Leukemia Patients
Rocha et al, N Engl J Med 2004;351:2276-85.
7. Bone Marrow or Peripheral Blood Stem Cells?
Stem Cell Trialists' Collaborative Group, JCO 2005
8. Pioneers in Cord Blood Transplantation
Eliane Gluckman
Paris
Pablo Rubenstein
New York John Wagner
Minneapolis
9. Survival after 0-3 Mismatched Unrelated UCB &
6/6 HLA-matched BMT in children
1.0 1.0
Proportion Surviving
0.8 0.8
0.6
BMT-TCD
0.6 UCBT 56%
Proportion
53%
Surviving
0.4 41% 0.4 UCBT 52%
BMT-MTX
0.2 0.2
p = .40 p > .80
0.0 0.0
0 6 12 18 24 0 6 12 18 24
Months Months
Patient analyses with match for age, diagnosis, and disease stage.
Barker et al, Blood. 2001 May 15;97(10):2957-61.
10. Probability of Neutrophil Recovery by UCB Graft Cell Dose
1.0
cell dose < 1.87*107/kg (n=23)
cell dose (1.87, 2.41) (n=21)
Probability of neutrophil recovery
0.8
cell dose > 2.41*107/kg (n=24)
0.6
p-value = 0.003
0.4
0.2
0.0
0 10 20 30 40 50 60
days after transplantation
No. at Risk: 68 66 53 26 6 1
Laughlin, MJ., et al., N Engl J Med 2001;344:1815-22
11. DFS for Acute Leukemia in CR
Single vs. Double UCBT
CY60/TBI1320
1.0
I I I I
Cumulative Proportion
0.8 double
I I
I
0.6 I I I
I
single
0.4
Double: Adults +
0.2 Adolescents
Single: Children
0.0
0 2 4 6 8 10 12
Months
12. PROBABILITY OF SURVIVAL
Impact of Cell dose and HLA mismatch
1.0
0.8
CB matched
PROBABILITY
0.6
CB 1 agmm (>2.5)
0.4 CB 2 agmm (>2.5)
0.2 CB 1 agmm (<2.5)
CB 2 agmm (<2.5)
0.0
0 1 2 3
YEARS
13. Mary Horowitz
CIBMTR University of Wisconsin
... ..
............... .
..
. .... .......... .
.......... . . .
. ..
. .... .. . . .. . .........
... ..........
. .. . .. .
. .
.. .. .
. .
.. ... ..
. ..
.
.
. ..
.... . . .... ...
.
..
135 staff including, 6 PhD statisticians, 14 MS statisticians, 11 MD-MS faculty;
Active program of statistical methodology research specifically focused on
transplant outcomes in addition to supporting clinical studies
14. Overall Survival
Pediatric Study
100
CB matched (n=36) 62%
Adjusted Probability, %
BM matched (n=116) 45%
80 CB 1-Ag MM high (n=157) 45%
60
40
20 CB 1-Ag MM low (n=44) 36%
CB 2-Ag MM (n=267) 33%
0
0 12 24 36 48 60
Months
Mjz06_13.ppt
15. Neutrophil Recovery
Pediatric Study
100
BM (n=492), 97%
CB matched (n=35), 86%
80 CB MM high dose (n=362), 79%
Probability, %
CB MM low dose (n=97), 64%
60
40
20
0
0 20 40 60 80 100
Days
CAL05_13.ppt
16. Acute Grade 2-4 GVHD
Pediatric Study
100
80
BM MM (n=123), 70%
Probability, %
60
BM matched (n=368), 50%
40
CB MM (n=454), 40%
20
CB matched (n=35), 20%
0
0 20 40 60 80 100
Days
CAL05_15.ppt
18. Treatment-related Mortality
Pediatric Study
100
80
Probability, %
CB 1-Ag MM low (n=44), 43%
BM MM (n=123), 40%
60
CB 2-Ag MM (n=267), 47%
40
CB 1-Ag MM high (n=157),
29%
20 BM matched (n=369), 26%
CB matched (n=35), 6%
0
0 12 24 36 48 60
Months
CAL05_27.ppt
19. Leukemia-free survival
Pediatric study
100
80
Probability, %
CB matched (n=35), 60%
60
CB 1-Ag MM high (n=157), 41%
40
BM matched (n=369), 40%
20 CB 1-Ag MM low (n=44), 36%
CB 2-Ag MM (n=267), 33%
BM MM (n=123), 30%
0
0 12 24 36 48 60
Months
CAL05_17.ppt
20. Overall Survival
Pediatric Study
100
80
Probability, %
CB matched (n=36), 62%
60
CB 1-Ag MM high (n=157), 45%
40
BM matched (n=369), 44%
20 BM MM (n=123), 40%
CB 1-Ag MM low (n=44), 35%
CB 2-Ag MM (n=267), 35%
0
0 12 24 36 48 60
Months
CAL05_20.ppt
21. The IPA/NIMA effect - Jon Van Rood
Mother Father NIMA = non inherited maternal antigens
IMA/NIMA IPA/NIPA
NIPA = non inherited paternal antigens
IMA = inherited maternal antigens
IPA = inherited paternal antigens
The mother develops B and T cell
immunity against the IPA of the
fetus, which is controlled by T reg.
Likewise, the fetus develop immunity
and T reg against the NIMA.
Immunity can be lifelong in both mother
and child.
Patient IMA/IPA
22. HSCT with a parental donor shows a differential effect of maternal
versus paternal donors on survival.
1.0
0.8
0.6
Mother donor N=47
Event
0.4
Free
Survival
0.2
Father donor N=71
0.0
p<0.0001
Years Follow-Up 0 1 2 3 4 5
# at risk: 118 38 29 28 28 28
M. Stern et al. Blood 2008
23. Identification of an acceptable mismatch
with the help of NIMA
van Rood et al. Pnas: 2009, 106, pp 19952
Patient A1, A2 - B7, B44
cord blood A1, A3 - B7, B44
mother of CB A1, A2 - B7, B8 NIMA=A2 and B8
Combining the NIMA A2 and B8 with the CB phenotype can
create for example the following Virtual CB phenotype:
A1, A2 / B7, B44
and 5 other Virtual Phenotypes (VP) if there is one substitution and
12 when there are two.
HLA typing of the mother created 16 different VPs!!
24. Transplant-Related Mortality
(Patients ≥ 10 Years Old)
80
% with TRM (Cum. Incid.)
2 MM, No NIMA Match Reference 290/488
60 2 MM, 1NIMA Match
1 MM, No NIMA Match Reference
40 1 MM, 1NIMA Match 20/41 RR=0.6, P= 0.012
20
0 Mismatch 4/22 RR=0.3 P = 0.011
0
0 1 2 3
Years Post-Transplant PNAS 2009 106 (47) p10952
25. Time to Absolute Neutrophil Count ≥ 500
100
(Cum. Incid)
0 Mismatch
80
1-2 MM, 1 NIMA Match
60
% with ANC 500
1-2 MM, No NIMA Match
40
20
0
0 7 14 21 28 35 42 56 70
days after transplant
Patients N RR p value
0 MM 15 3.8 <0.001
1-2 MM,1 NIMA Match 18 1.9 0.031
1-2 MM, No NIMA Match 219 reference
26. Relapse
(Patients with Myeloid Diseases)
HLA MM/ NIMA RR P
2 MM/No NIMA (n = 343) 0.7 0.075
1 MN/No NIMA (n =193) Reference
40
% with Relapse (Cum. Incid.)
2 MM/NIMA Match (n = 31) 0.7 0.448
1 MM/NIMA Match (n = 13) 0.2 0.074
0 MM (n = 33) 0.7 0.306
1 MM, No NIMA Match
30 0 Mismatch
2 MM, NIMA Match
20
2 MM, No NIMA Match
10 1 MM, NIMA Match
0
0 1 2 3
Years Post-Transplant PNAS 2009, 106, pp 19952
27. Acknowledgements
NYBC - NCBP Europdonor Foundation
• Andromachi Scaradavou • Henk van der Zanden
• Pablo Rubinstein • Machteld Oudshoorn
• C. Carrier, C. Carpenter • Jack Bakker,Angelo Melis
• NCBP Program Staff
• Frans Claas
• Transplant centers/
physicians/data managers/
patients
• Donating Mothers • Eurotransplant Foundation
• Jacqueline Smits
• Cladd Stevens
28. Current Status
Stem Cell Products provided for unrelated transplantation
18,000
16,000
2008 2009
Number of donations
14,000
Bone Marrow 3,221 3,445
12,000
10,000 PBSC 7,260 8,162
8,000
Cord Blood Units 3,522 3,749
6,000
4,000
2,000
0
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
Year
BM donations PBSC donations Cord Blood Units Provided
29. % Patients Transplanted in Relation
to Searches Requested
Red: 0-10%
Yellow: 10-30%
Orange: 30-50%
Green: > 50% Analyzed from WMDA Annual Report 2009
30. The ABMDR is the best place to search for Australian Patients
These are the best registries to
search for Australian patients
Chance of finding a donor for an AUSTRALIAN patient
32. In 2009
18 Products a Day
6,461 Products
crossed a Border
Percentage of bone marrow/PBSC donations provided for
national and international patients
75
65 69.7 69.4 69.1
67.1 66.3 67.5
65.6 64.7
61.1 61.2
Percentage (%)
55
58.0
56.2 55.1
45
43.8 44.9
35
38.8 42.0
38.9
34.4 35.3
32.9 33.7 32.5
30.3 30.6 30.9
25
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Year
Donations to international recipients Donations to national recipients
33. In 2010, 149 cord blood banks
participated worldwide
Number of CBUs provided for unrelated transplantation
4,500
2010 2009
4,000
Number of cord blood units
CBUs provided 4,054 3,792
3,500
3,000
2,500
2,000
1,500
1,000
500
0
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
Year
No information provided Units provided for adults Units provided for children
34. Degree of matching of the cord blood units provided for
children (N=1,286 units)
0 mismatched
664
1 mismatched
600 2 mismatched
Number of cord blood units
3 or more
500
not specified
400 299
245
300
204
200
100 6
0
Degree of matching of the cord blood units provided for
adults (N=2,768 units)
0 mismatched
1,213 1 mismatched
1,200 2 mismatched
Number of cord blood units
3 or more
1,000 830 not specified
771
800
600
400
245
200 20
0
35. International exchange of cord
blood products is increasing
Number of cord blood units provided for national and international
patients
3,000
2,726
2,537
2,321
2,500
Number of Cord Blood Units
2,207
2,000 1,862
1,710
1,368 1,255 1,328
1,500 1,235
1,213
1,098
1,000 829
625 652
510
500 346 372 387
284
146 192 175
129
0
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Year
Provided Internationally Provided Nationally
In 2010: 3.63 cord blood products passing an international border a day
36. NATIONAL MARROW DONOR PROGRAM® 36
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry®
38. Over 70% of the CBUs shipped for
adult patients have a TNC >150
Cord blood shipments by TNC for adult patients
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
2004 2005 2006 2007 2008 2009 2010
<90 90-119 120-149 150-199 200-249 250-300 >300
39. 2010 Inventory and shipments
TNC of BMDW inventory as of January 1,
2011
1%
2% 0.002%
6%
10%
12%
36%
33% TNC of the CBU products shipped in 2010
2%
0.003
6%
<50 50-89 90-124 125-149 8% 14%
150-199 200-249 250-300 >300
20%
18%
76% of the shipments came
from 25% of the available 32%
inventory
<50 50-89 90-124 125-149
150-199 200-249 250-300 >300
40. Shipping rate of the units listed
in BMDW based on TNC
(units shipped/units available)
TNC Percentage(%)
< 50 0.03
50-89 0.09
90-124 0.3
125-149 1.0
150-199 2.3
200-249 6.3
250-300 10.5
>300 17.0
41. NATIONAL MARROW DONOR PROGRAM® 41
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry®
42.
43. 2010
WHO Guiding Principles on
Human Cell, Tissue and Organ Transplantation
World Health Assembly - 22 May 2010
1.
1. Consentfor deceased donor's donation
Consent for deceased donor's donation
2.
2. No conflictfor death determination
No conflict for death determination
3.
3. Deceasedbut also consenting live donors
Deceased but also consenting live donors
4.
4. Protectionof minors and incompetent persons
Protection of minors and incompetent persons
5.
5. No sale or purchase
No sale or purchase
6.
6. Promotionof donation nono advertisingbrokering
Promotion of donation advertising nor nor brokering
7.
7. Responsibility on origintransplant
Responsibility on origin of of transplant
8.
8. Justifiable professional fees
Justifiable professional fees
9. Allocationrules
9. Allocation rules
10. Quality safety efficacy of procedures and transplants
10. Quality safety efficacy of procedures and transplants
11. Transparency and confidentiality
11. Transparency and confidentiality
44. 2010 WHO Guiding Principles on
Human Cell, Tissue and Organ Transplantation
GP 5 Free donation and no purchase of human transplant as such,
but cost & expenditures recovery
GP 6 GP 7 GP 8
GP 3 Promoting Responsibility Justifiable fees
Maximizing DD No advertising for transplant origin
Protecting LD
GP 2 GP 4 GP 9
Death Δγ Protecting the Equitable allocation
No conflict incompetent
GP 1
Consent DD
Donor Process Recipient
GP 10 Monitoring long term outcomes. Quality & safety of procedures & products
GP 11 Transparency, openness to scrutiny, anonymity
45. WHO Guiding Principles on
2010 Human Cell, Tissue Long term
Short and and Organ Transplantation
Donor Outcomes 2010
World Health Assembly - 22 May
Recipient Outcomes
Guiding Principle 10
Quality systems
Traceability
Vigilance
Adverse event reporting
46. WHO Guiding Principles on
2010 Human Cell, Tissue and Organ Transplantation
World Health Assembly - 22 May 2010
Transparency
Open to Scrutiny
Maintaining privacy of
Donors and Recipients
48. The blood safety paradigm doesn’t translate to Organs & Cells.
What is the problem?
Volume of activity Scarcity of Donors
Blood donations are in the Blood donors can be
millions in many countries replaced
Organ donations are in the Organ donors are very
thousands in only a very scarce
few countries
Hemopoetic stem cell
Hemopoetic stem cell donors are usually unique
donations are even fewer for each recipient
Mortality rates on organ transplant waiting lists are substantial
Unavoidable mortality rates from transplantation are substantial
Risks from transmission of disease are very small under standard procedures
Regulation risk: causing more deaths than saved
49. The effect of putting the Barriers
up
+++
500
400
In Country
300 National
Import
200
Export
100
0
Out of Country
-100
-200
-300
-400
-500 +
50. The effect of putting the Barriers
up
+++
500
400
In Country
300 Import
National
200
Export
100
0
Out of Country
-100
-200
-300
-400
-500 +
54. Analyze: where are CBUs
used for transplantation?
Number of Cord Blood Units shipped to each continent over time
1,600
Number of CBUs provided
1,400
1,200
1,000
800
600
400
200
0
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Year
Asia Australia Europe North America South America Africa
35% of the CBUs shipped are shipped to North America
33% of the CBUs shipped are shipped to Asia
55. Guidance for Industry
Minimally Manipulated, Unrelated Allogeneic
Placental/Umbilical Cord Blood Intended for Hematopoietic
Reconstitution for Specified Indications
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
October 2009
1 This guidance applies to HPC-Cs manufactured by U.S. cord blood establishments and non-
U.S. cord blood establishments that distribute cord blood in the U.S. However, some non-U.S.
cord blood establishments that participate in international registries may not apply for licensure
Importation and use of unlicensed placental/umbilical cord
of their products. Importation and use of unlicensed placental/umbilical cord stem/progenitor
cell products from non-U.S. cord blood establishments would be acceptable under an
stem/progenitor cell products from non-U.S. cord bloodan affiliated
Investigational New Drug (IND) application held by the non-U.S. establishment,
establishments the U.S. transplant center, or a registry. Also, certain HPC-Cs
U.S. establishment, would be acceptable under an Investigational New
manufactured in the U.S. may not be licensed but could be listed in registries and made
Drug (IND) applicationan IND. Additional non-U.S. establishment, anof
available for clinical use under held by the recommendations regarding submission
affiliated U.S. establishment, provided in the companion draft guidanceor a
INDs for certain unlicensed HPC-Cs are the U.S. transplant center, entitled
“Guidance for Industry and FDA Staff: Investigational New Drug Applications (INDs) for
registry. Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for
Minimally
Hematopoietic Reconstitution for Specified Indications).”
56. Europe
Reliant upon each national competent
authority.....
EUROPEAN DIRECTIVE 2004/23/EC; article 9
Import/export of human tissues and cells
Member States and tissue establishments that receive such
imports from third countries shall ensure that they meet
standards of quality and safety.
57. Legislation to enact European Directive on HSC
August 2011
Not standardised
Legislated
Not Legislated
59. Quality, efficacy and
safety
International Standards
Accreditation and Audit
Data collection and analysis
Donor safety - SEAR
Product safety - SPEAR
Recipient safety – Outcome
databases
This will not be enough – but it will
60. 2009 – 9 events reported to the WMDA (to date) • 2009 – 7 events reported to the WMDA (to date). All except 1 prior to
– 8 incidents from donations before 2009, 1 in 2009 2009 (4 - 2008, 1 - 2006, 1 - 1996):
(3 - 2008, 3 - 2006, 1 - 2003, 1-1997): – Donor blood group incorrect on label (all other identifiers
• 5 cancers correct)
– Breast/ brain (benign)/NHL post BM – Incorrect product collected by courier (2 harvested on same day).
– Lung/ hepatoma post PBSC (hepatoma had 3 doses of Identified and rectified before courier left airport
GCSF - not collected due to patient factors) – Cord unit arrived partially thawed. 28% viability in segment. Not
• 1 cauda equina syndrome post BM infused
• 1 severe groin bruising post groin line for DLI – Clots in apheresis bag - engrafted
• 1 faint following tubing rupture during PBSC (target dose – Rupture of tubing on cell separator. Collection abandoned. Target
collected on second day) achieved on day 2
• 1 fat embolism post GA and BM harvest - full recovery – 2 donor derived malignancies
• Patient with MDS (Tx 04/06) diagnosed with CML in 11/08.
Donor diagnosed with CML 05/08
• Patient with CML (Tx 06/96) diagnosed with mantle cell
lymphoma in 05/08. Donor diagnosed with MCL 098/08
72. Challenges
1. Keeping open access for all recipients to all
HSC’s
2. Keeping the costs of HSC products down
3. Ensuring individual patient risk benefit
decisions
4. Maintaining small market share tests and
products
5. Maintaining rapid access search systems
6. Working with regulators and governments to
recognize the global nature of the issues but not
being afraid to call them to task
7. Establishing a coding and labelling system
This slide shows graphically what happens. A single mismatch which is compensated by a single NIMA match, results in a TRM which is near identical to a zero mismatch. Two HLA mismatches compensated by a single NIMA match results in a TRM identical to a single mismatch.