Institute of MedicineCommittee on Establishing a National Cord Blood Stem Cell Bank Program 2nd Publ

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Institute of Medicine-Committee on Establishing a
National Cord Blood Stem Cell Bank Program 2nd
Public Meeting (8/18-19/2004)UNRELATED CORD
BLOOD TRANSPLANTATION OUTCOMES
Presented by Pablo Rubinstein, M.D., on behalf
of The National Cord Blood Program New York
Blood Center
NYBC NCBP
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(No Transcript)
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MYELOID ENGRAFTMENTHLA match and TNC doseare
the major Graft-Associated Variables
NYBC NCBP
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Myeloid Engraftmentby HLA Match and TNC Dose (x
107/kg)
100
5.0-9.9
10
6/6
5/6
80
4/6
2.5-4.9
3/6
60
with ANC ? 500 (K-M)
40
HLA Match
TNC Dose
Cox Regr. RR P
Cox Regr. RR P
20
6/6 (n 66) 1.5 0.005
10 (n 209) 1.9 5/6 (n 463) 0.9 0.4
5.0-9.9 (n 337) 1.2 0.014
4/6 (n 685) Reference
2.5-4.9 (n 443) Reference
3/6 (n 79) 0.7 0.021
14 28 42 56 70
14 28 42 56 70
Days Post-Transplant
NYBC NCBP
7/30/04
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Myeloid Engraftment in Patients withTNC Dose
10.0 x 107/kg
100
P 0.7
80
20.0
60
with ANC ? 500 (Kaplan-Meier)
10.0-19.9
40
20
Cox Regression RR P
20.0 (n 41) 1.10 0.7
10.0-19.9 (n 168) Reference
7 14 21 28 35 42 49
56 63 70 77
Days Post-Transplant
NYBC NCBP
7/30/04
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Multivariate Analysisof Myeloid Engraftment
TNC/kg (n) RR P
10.0 x 107 (n207) 1.9 5.0-9.9 x 107 (n333) 1.2 0.010
2.5-4.9 x 107 (n437) Reference
HLA Match (n) RR P
6/6 (n66) 1.5 0.009
5/6 (n463) 0.9 0.4
4/6 (n685) Reference
3/6 (n79) 0.7 0.027
NYBC NCBP
7/30/04
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Cell dose surrogate fortrue hematopoietic
stem cell dose
Total Nucleated Cells (TNC)
White Blood Cells (WBC)
Mononuclear Cells (MNC)
Colony Forming Unit (CFU)
CD34 Cells (CD34)
Lymphocytes Monocytes NRBC
NYBC NCBP
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Myeloid Engraftment byNucleated RBC Dose (x
107/kg)
100
P 80
4.0
2.0-3.9
1.0-1.9
60
with ANC ? 500 (Kaplan-Meier)
40
Cox Regression RR P
? 4.0 (n 401) 1.7 20
2.0-3.9 (n 244) 1.4 0.003
1.0-1.9 (n 234) Reference
7 14 21 28 35 42 49
56 63 70 77
Days Post-Transplant
NYBC NCBP
(Updated from Blood, 2002)
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Univariate Analysisof Myeloid Engraftment
Variable (units, number) RR P
TNC (x 107/kg, n1297) 1.027 WBC (x 107/kg, n1213) 1.029 Neuts (x 107/kg, n1297) 1.004 Lymphs (x 107/kg, n1297) 1.006 Monos (x 107/kg, n1297) 1.025 NRBC (x 107/kg, n1213) 1.017 Rounded to nearest 107
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Multivariate Analysesof Myeloid Engraftment
Variable (x 107/kg, n1213)
RR P
Neuts 0.998 0.3
Lymphs 0.994 0.08
Monos 1.047 NRBC 1.015 NYBC NCBP
7/30/04
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Myeloid Engraftment by CFU Dose and CD34 Cell
Dose (x 104/kg)
100
10.0-19.9
20
40
20.0-39.9
80
5.0-9.9
10.0-19.9
60
with ANC ? 500 (K-M)
40
CFU Dose
CD34 Dose
Cox Regr. RR P
Cox Regr. RR P
20
20 (n 77) 1.8 40 (n 31) 2.1 0.003
10-19 (n 120) 1.4 0.019
20-39 (n 51) 1.9 0.004
5-9 (n 144) Reference
10-19 (n 59) Reference
14 28 42 56 70
14 28 42 56 70
Days Post-Transplant
NYBC NCBP
7/30/04
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Multivariate Analysesof Myeloid Engraftment
Variable (TNC x 107/kg CFU x
104/kg, n451)
RR P
TNC 0.980 0.2
CFU 1.036 Variable (TNC x 107/kg CD34 x 104/kg,
n189)
RR P
TNC 0.988 0.6
CD34 1.015 0.001
NYBC NCBP
7/30/04
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Myeloid Engraftment byPost-thaw TNC (x 107/kg)
100
P 5.0-9.9
80
10.0
2.5-4.9
60
with ANC ? 500 (Kaplan-Meier)
40
Cox Regression RR P
? 10.0 (n 443) 1.9 20
5.0-9.9 (n 229) 1.3 0.016
2.5-4.9 (n 353) Reference
7 14 21 28 35 42 49
56 63 70 77
Days Post-Transplant
NYBC NCBP
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Multivariate Analysisof Myeloid Engraftment
Variable (number) RR P
Pre-Freeze TNC (n1111) 0.968 0.014
Post-Thaw TNC (n1111) 1.097 NYBC NCBP
7/30/04
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HLA

• HLA Matching Level -A and -B Serological
  Split Level (DNA-SSP low-medium
  resolution) -DRB1 Allele Level (DNA
  Sequence-Based Typing)
• Confirmatory Typing on Segment Integral
  to Freezing Bag

NYBC NCBP
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Myeloid Engraftment in Patients with5/6 HLA
Match by Mismatch Location
100
P 0.4
A
B
80
DRB1
60
with ANC ? 500 (Kaplan-Meier)
HLA-A and B serological level, HLA-DRB1 DNA
allele level
40
Cox Regression RR P
20
DRB1 (n 130) 0.84 0.3
B (n 196) 1.02 0.9
A (n 138) Reference
7 14 21 28 35 42 49
56 63 70 77
Days Post-Transplant
NYBC NCBP
7/30/04
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Myeloid Engraftment in Patients with5/6 HLA
Match by HLA-C Match
100
P 0.9
80
C Mismatch
C Match
60
with ANC ? 500 (Kaplan-Meier)
40
HLA-C DNA High resolution SSP level
20
Cox Regression RR P
C Mismatch (n 167) 1.01 0.9
C Match (n 125) Reference
7 14 21 28 35 42 49
56 63 70 77
Days Post-Transplant
NYBC NCBP
7/30/04
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5/6 HLA Matches Blanks can be One-Way
Mismatches
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One HLA Mismatch inBoth Directions (Two-Way)
A B DRB1
Patient 3, 32 14, 35 0101,
0401
CB Unit 3, 32 14, 27 0101,
0401
Patient and Unit Heterozygous at the mismatched
locus, HLA B
NYBC NCBP
7/04
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Single One-Way Mismatch inGvHD Direction
A B DRB1
Patient 2, 24 44, 51 1104, 1201
CB Unit 2, 24 44, 51 1104, __
Unit has a Blank at DRB1 locus (Homozygous for
DRB1 1104)
NYBC NCBP
7/04
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Single One-Way Mismatch inRejection Direction
A B DR
Patient 2, 24 35, __ 0401,1401
CB Unit 2, 24 35, 40 0401,1401
Patient has a Blank at B locus (Homozygous for
B 35)
NYBC NCBP
7/04
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Myeloid Engraftment in US Patients withSingle
HLA Mismatch, One-Way or Two-Way
100
P 0.03
80
GvHD (Unit Blank)
Both Directions (No Blanks)
60
Rejection (Patient Blank)
with ANC ? 500 (Kaplan-Meier)
40
Cox Regression RR P
20
GvHD (n 41) 1.27 0.2
Rejection (n 31) 0.56 0.03
Both (n 278) Reference
7 14 21 28 35 42 49
56 63 70 77
Days Post-Transplant
NYBC NCBP
7/30/04
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HLA and SURVIVAL
NYBC NCBP
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Survival by HLA Match
100
Cox Regress. RR P
P 0.0001
6/6 (n 67) 0.49 5/6 (n 488) 0.82 0.008
80
4/6 (n 714) Reference
3/6 (n 82) 1.12 0.4
60
Surviving (Kaplan-Meier)
6/6
5/6
40
4/6
3/6
20
HLA-A and B serological level, HLA-DRB1 DNA
allele level
6/6 vs. 5/6, P 0.013
1 2
3 4 5
Years Post-Transplant
NYBC NCBP
7/30/04
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Survival in Patients with 5/6 Graftsby Mismatch
Location
100
Cox Regress. RR P
P 0.2
DR (n 135) 1.17 0.3
B (n 206) 0.91 0.5
80
A (n 149) Reference
60
Surviving (Kaplan-Meier)
B
A
40
DR
20
1 2
3 4 5
Years Post-Transplant
NYBC NCBP
7/30/04
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Survival in US Patients with 5/6 Graftsby
Mismatch Location
100
Cox Regression RR P
P 0.13
A or B (n 254) Reference
High Res. DR (n 22) 1.63 0.07
80
Low Res. DR (n 113) 1.17 0.3
60
Surviving (Kaplan-Meier)
A or B
40
Low Res. DR
20
High Res. DR
1 2
3 4 5
Years Post-Transplant
NYBC NCBP
7/30/04
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Survival in US Patients with 5/6 Grafts by HLA-C
Mismatch
100
P 0.8
Cox Regression RR P
C Mismatch (n 155) 1.04 0.8
80
C Match (n 137) Reference
60
Surviving (Kaplan-Meier)
C Match
40
C Mismatch
20
1 2
3 4 5
Years Post-Transplant
NYBC NCBP
7/30/04
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Survival in US Patients with 5/6 Grafts by HLA-A
or -B Split Match/Mismatch
100
P 0.9
Cox Regression RR P
Split Mismatch (n 21) 0.99 0.9
80
Split Match (n 104) 0.93 0.6
No Split Ag (n 356) Reference
60
Split Mismatch
Surviving (Kaplan-Meier)
Split Match
40
No Split Antigen
20
1 2
3
Years Post-Transplant
NYBC NCBP
7/30/04
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Survival Other Influences
30
Leukemia Survival by Risk(IBMRT Risk Criteria
for ALL, AML, CML)
Risk Group RR P
Not ALL, AML, CML Reference ALL, AML, or CML
80
Cox Regr.
Low Risk 1.1 0.3
Interm. Risk 1.2 0.09
60
Advanced 1.8 Survival
Other (n444)
43.2
40
40.5
Early (n178)
34.5
Intermediate (n318)
20
19.4
Advanced (n252)
P 0 1
2 3
Years Post-Transplant
7/30/04
NYBC NCBP
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Survival by PatientsPre-TXP CMV Antibody
Pre-TXP CMV Ab RR P
80
Cox Regr.
Negative Reference
Positive 1.3 0.001
60
Survival
Negative (n581)
40
39.0
29.8
Positive (n511)
20
P 0.0006
0 1
2 3
Years Post-Transplant
7/30/04
NYBC NCBP
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Survival by ABO Match
Patient/Unit ABO RR P
Match Reference
Cox Regr.
80
Minor Mismatch 1.01 0.9
Major Mismatch 1.05 0.6
Direction of Graft Rejection
60
Survival
Match (n405)
Minor Mismatch (n285)
40
35.0
35.5
34.7
Major Mismatch (n388)
20
0 1
2 3
Years Post-Transplant
7/30/04
NYBC NCBP
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Survival by Length of Time in Storage
In Storage RR P
Cox Regr.
80
1-2 Years 1.07 0.5
3-4 Years 1.13 0.2
5-10 Years 1.09 0.5
(Range 32 days 10 years)
60
Survival
1-2 Years (n619)
40
3-4 Years (n354)
5-10 Years (n146)
20
0 1
2 3
Years Post-Transplant
7/30/04
NYBC NCBP
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Data from Adult Recipients
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Diagnosis in 391 AdultsGiven NYBC CB Units
1994-2003
Leukemia (n 317)

ALL (n 83)
AML (n 129)
41 Advanced
CML (n 101)
CLL (n 4)
Myelodysplasia (n 18)
Lymphoma (n 28)
Severe Aplastic Anemia (n 9)
Genetic (n 11)
Other (n 8)
NYBC NCBP
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Characteristics of 391 AdultsGiven NYBC CB Units
Age (range 16-70, mean 33.5)
16-24 years 130 (33.2) 25-39
years 135 (34.5) 40 years
126 (32.2)
Ethnicity
Asian 14
(3.9) African-American 54
(15.0) Hispanic 48
(13.3) Middle Eastern 6
(1.7) Native American 2
(0.6) Caucasian 236
(65.6) Unknown 31 ---
Prior Transplant 47 (13)
NYBC NCBP
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Graft Characteristics
TNC Dose (x107/kg) Mean 2.4 N
0.7-2.4 242
(61.9) 2.5-4.9 144
(36.8) 5.0 5
(1.3)
HLA Mismatch
0 (6/6 match) 8 (2.1) 1
(5/6 match) 97 (24.9) 2
(4/6 match) 248 (63.6) 3
(3/6 match) 37 (9.5)
1 not typed by high resolution
NYBC NCBP
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HLA Mismatch Level in Children and Adults
P 60
16 yrs.
40
of Age Group
20
0 (6/6) 1 (5/6) 2 (4/6)
3 (3/6)
HLA Mismatches
NYBC NCBP
39
Myeloid Engraftment and TNC Dose
100
5.0
80
2.5-4.9
60
with ANC ? 500 (Cumulative Incidence)
40
Cox Regression RR P
20
5.0 x 107 (n 4) 1.9 0.3
2.5-4.9 x 107 (n 124) 1.5 0.004
7 14 21 28 35 42 49
56 63 70 77
Days Post-Transplant
NYBC NCBP
7/30/04
40
Patients with 0-3 HLA MismatchEngraftment by
Mismatches in Rejection Direction
100
0 (6/6 No rejection mismatch)
80
1
60
2
with ANC ? 500 (Cumulative Incidence)
3
40
Cox Regression RR P
0 (n 17) 2.4 0.001
20
1 (n 108) 1.1 0.6
2 (n 193) Reference
3 ( (n 23) 0.7 0.2
7 14 21 28 35 42 49
56 63 70 77
Days Post-Transplant
NYBC NCBP
41
Multivariate Analysisof Myeloid Engraftment in
Adults
Variable (n) RR P
TNC/Kg
2.5-4.9 x 107 (n100) 1.5 0.005
0.7-2.4 x 107 (n162) Reference
Rejection Mismatch
0 (n15) 2.1 0.01
1 (n76) 1.0 0.9
2 (n155) Reference
3 (n16) 0.7 0.4
TBI/Fludarabine
TBI Flud. (n24) 1.9 0.01
Flud. Only (n17) 0.8 0.6
Other (n59) 0.8 0.3
TBI Only (n162) Reference
Methotrexate
Methotrexate (n33) 0.5 0.02
No MTX (n229) Reference
Multiple CB Unit N.S.
NYBC NCBP
42
Data in Adult PatientsSURVIVAL
43
Survival in Adult Patients
100
80
60
Surviving (Kaplan-Meier)
40
30.2
25.5
23.0
20
N 361
0 1 2
3 4 5
Years Post-Transplant
NYBC NCBP
44
Survival in Adults by TNC Dose
100
80
60
5.0
Surviving (Kaplan-Meier)
50
2.5 - 4.9
40
34
28
TNC x 107/kg RR P
0.7 - 2.4
20
5.0 (n 5) 0.5 0.2
Cox Regr.
2.5 - 4.9 (n 128) 0.8 0.3
0.7 2.4 (n 225) Reference
0 1 3 6
9 12
Months Post-Transplant
NYBC NCBP
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All Adults (0-3 HLA Mismatch)Survival by
Mismatches in Rejection Direction
100
0 (6/6 0 rejection mismatch)
80
68
60
Surviving (Kaplan-Meier)
40
1
33
Rejection Mismatch RR P
27
2
0 (n 17) 0.3 0.005
20
20
1 (n 112) 0.8 0.2
3
Cox Regr.
2 (n 203) Reference
3 (n 25) 1.2 0.5
0 1 3 6
9 12
Months Post-Transplant
NYBC NCBP
46
Survival in All Patients with 0 Rejection
Mismatch by Age Group
100
16 years (mean TNC 2.3 x 107/kg)
80
68
0-15 years (mean TNC 7.9 x 107/kg)
66
60
Surviving (Kaplan-Meier)
40
Age Group RR P
20
16 (n 17) 0.8 0.7
Cox Regr.
0 - 15 (n 101) Reference
0 1 3 6
9 12
Months Post-Transplant
NYBC NCBP
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Survival in Adults by Stage of Leukemia (IBMTR
Criteria)
100
80
60
Other Diseases
Surviving (Kaplan-Meier)
Early Leukemia
42
40
37
30
Stage of Disease RR P
Intermediate
Advanced (n 119) 1.6 0.013
20
21
Cox Regr.
Advanced
Intermediate (n 89) 1.1 0.7
Early (n 76) 1.0 0.9
Other (n 67) Reference
0 1 3 6
9 12
Months Post-Transplant
NYBC NCBP
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Survival in Adults by Number of CB Units
100
80
60
Surviving (Kaplan-Meier)
2 CB Units
40
40
29
1 CB Unit
20
Number of CB Units RR P
2 CB Units (n 36) 0.6 0.052
Cox Regr.
1 CB Unit (n 322) Reference
0 1 3 6
9 12
Months Post-Transplant
NYBC NCBP
49
Survival in Adults by Prior Transplant
100
80
60
Surviving (Kaplan-Meier)
Prior Transplant
40
36
30
None
20
Prior Transplant RR P
Prior Transplant (n 49) 0.9 0.7
Cox Regr.
None (n 290) Reference
0 1 3 6
9 12
Months Post-Transplant
NYBC NCBP
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Multivariate Analysis of 1 Year Survival in Adult
Patients (1)
Variable (n) RR P
TNC/Kg
2.5-4.9 x 107 (n125) 0.8 0.051
0.7-2.4 x 107 (n217) Reference
Rejection Mismatch
0 (n17) 0.3 0.011
1 (n107) 0.9 0.3
2 (n194) Reference
3 (n24) 1.1
0.6
2 CB Units (n32) 0.8 0.3
Multiple CB Unit
1 CB Unit (n310) Reference
Center Experience
10 Adults (n186) Reference
Advanced (n111) 1.4 0.011
Risk
All Others (n231) Reference
NYBC NCBP
51
Multivariate Analysis of 1 Year Survival in Adult
Patients (2)
Variable (n) RR P
2.5-4.9 x 107 (n121) 0.8 0.07
TNC/Kg
0.7-2.4 x 107 (n206) Reference
Rejection Mismatch
0 (n17) 0.4 0.023
1 (n105) 0.9 0.3
2 (n182) Reference
3 (n23) 1.0
0.9
TBI/Fludarabine
Other (n74) 1.0 0.8
TBI/Flud. (n26) 0.4 0.009

Flud. Only (n18) 0.7 0.2
TBI Only (n209) Reference
Center Experience
10 Adults (n182) Reference
Advanced (n110) 1.4 0.014
Risk
All Others (n217) Reference
NYBC NCBP