The MSKCC Experience SCID_OReilly.pdf · SCID defect of 68 consecutive recipients of a Parental HLA...
Transcript of The MSKCC Experience SCID_OReilly.pdf · SCID defect of 68 consecutive recipients of a Parental HLA...
The MSKCC Experience
SBA-E- T Cell Depleted HLA Haploidentical Parental
Marrow TransplantsFor
Severe Combined Immunodeficiencies
METHOD OF T-CELL DEPLETION CELLS DEPLETED LOG T-CELL DEPLETION
MoAb CD2, CD3, CD5, or CD6 T 1-2.5
MoAb CD4 or CD8 T 1-2
T10B9 (TCR) + Cplt T 1.0-1.5
Anti-CD5 Ricin A-chain Immunotoxin T 1.5-2.0
Immunomagnetic separation (CD3-CD8) T 2
Rat MoAb Campath-1 (CD52) + Human Cplt T, B 1.7-2.5
Multiple E-rosetting depletion T, NK, B 1.5-2.0
Counterflow Elutriation T, +/- Fixed: 1.5-3.0
Soybean Agglutinin + E-rosetting T, NK, B 2.5-3.0
CellPro CD34+ T 1.5Isolex CD34+ T 2
Milteny T 3.0-4.0
T-CELL DEPLETION METHODS
DFS OF AML CR1 & CR2; HLA IDENTICAL RELATED,
TBI/THIO/CY/ATG
00.10.20.30.40.50.60.70.80.9
1
0 12 24 36 48 60 72 84 96 108 120
MONTHS POST TRANSPLANT
PRO
POR
TIO
63.5 % N = 14, CR 2
73.4 % N = 46, CR 1
CR 1 =9% CR2 = 12%PROBABILITY OF RELAPSE
00.10.20.30.40.50.60.70.80.9
1
0 12 24 36 48 60 72 84 96 108 120
MONTHS POST TRANSPLANTPR
OPO
RT
IO
62.0 % AGE > 40 years, N = 19
80.4 % AGE 18- 40 years, N = 26
00.10.20.30.40.50.60.70.80.9
1
0 12 24 36 48 60 72 84 96 108 120
MONTHS POST TRANSPLANTPR
OPO
RT
IO
62.0 % AGE > 40 years, N = 19
80.4 % AGE 18- 40 years, N = 26
DFS OF AML CR1; HLA IDENTICAL RELATED
TBI/THIO/CY/ATG; LSBMT; BY AGE
DFS OF Acute Leukemia CR1/CR2, UNRELATEDPEDIACTRIC PATIENTS BY HLA TYPE, MSKCC
0
0.2
0.4
0.6
0.8
1
0 12 24 36 48 60 72 84 96 108
MONTHS POST UNRELATED TRANSPLANT
PRO
POR
TIO
73.9 % Match, N=14
77.8 % Mismatch, N=9
Mismatched T-Depleted BMT for SCID
62 Patients No cytoreduction
4 early deaths
58 evaluable
10 No Eng
48 T cell Eng
56 Patients No cytoreduction
34 Patients BU/Cy
22 Patients Other Regimens
2 early
deaths
32 T cell Eng
2 early
deaths
14 T cell Eng
6 No Eng
118 Patients
Patients Transplanted Without Cytoreduction
Composite of Engraftment and Function by Cytoreduction
Response to Primary Transplant
Gamma chain defect
ADA-
JAK3
Omenn's
Ret Dys
Capping def
Aut Rec-unknown defect
Unk
SL dwarf
Ect Dysplasia
SCID defect of 68 consecutive recipients of a Parental HLA Haploidentical TCD BMT MSKCC 1980-2004, n=68
n=14B+ SCID (4)NK+SCID (5)NK+B+ (4)MDS,SCID (1)
Transplants For SCIDIncidence of GVHD Post SBA-E- BMT From Parental Donors
Host Unique Eng+ Acute GVHD Chronic HLA Disparities N Eval. I II-III GVHD
1 3 3 0 0 0
2 14 14 0 0 0
3 51 46 3 2 0
TOTAL 68 63 3 2 0
SCIDResults of HLA Haploidentical
SBA-E- TCD Parental Marrow GraftsTotal Consecutive Cases: 68 Surviving with Reconstitution 48 Dead 20
Preparation For Primary Graft
No Myeloablation Ablation
Total Patients: 40 28
Early Deaths:
Pre Engraftment 7 (17%) 2 ( 7%)
Post Engraftment 2 ( 5%) 3 (11%)
Late Deaths: 6 (15%) 0 ( 0%)
TOTAL: 15 (37.5%) 5 (18%)
Survival at 15 Years for SCID Patients who Received a Mismatched T-Depleted BMT
0
0.2
0.4
0.6
0.8
1
0 3 6 9 12 15
Time Post Transplant (Years)
Prop
ortio
n
OS = 71.75% n=68
Survival at 15 Years for SCID Patients who Received a Mismatched T-Depleted BMT
Survival at 15 Years by SCID Variant Mismatched T-Depleted BMT
0
0.2
0.4
0.6
0.8
1
0 3 6 9 12 15
Time Post Transplant (Years)
Prop
ortio
n
ADA Deficient, OS = 66.67% n=9
Auto Recessive, OS = 87.50% n=8
Inheritance Unknown, OS = 52.50% n=15
X-Linked, OS = 75.75% n=18
Other, OS = 81.73% n=18
Survival at 15 Years by SCID Variant Mismatched T-Depleted BMT
Survival at 15 Years of SCID Patients Transplanted at 3 months of Age Mismatched T-Depleted BMT
0
0.2
0.4
0.6
0.8
1
0 3 6 9 12 15
Time Post Transplant (Years)
Prop
ortio
n
OS >3 months = 69.15% n=49
OS <=3 months = 78.29% n=19
p=.5964
Survival at 15 Years of SCID Patients by Infection Mismatched T-Depleted BMT
0
0.2
0.4
0.6
0.8
1
0 3 6 9 12 15
Time Post Transplant (Years)
Prop
ortio
ln
No Infection prior to BMT, 76.73% n=32
Yes Infection prior to BMT, 68.20% n=36
p=.3229
Survival at 15 Years of SCID Patients Transplanted at 3 months of Age
Mismatched T-Depleted BMT
Survival at 15 Years of SCID Patients by Infection
Mismatched T-Depleted BMT
1
10
100
1000
100000-
3m3-
6m6-
9m9-
12m
12-1
8m18
-24m
24-3
6m36
-48m
48-6
0m60
-72m
0-3m
3-6m
6-9m
9-12
m12
-18m
18-2
4m24
-36m
36-4
8m48
-60m
60-7
2m
10th-50th-90th CD3 cell counts/ul
No cytoreduction, n=25 With cytoreduction, n=26
CD
3 ce
ll/ul
Months post TCD MM related BMT for SCID
1
10
100
1000
100000-3
m3-6
m6-9
m9-1
2m12
-18m
18-24
m24
-36m
36-48
m48
-60m
0-3m
3-6m
6-9m
9-12m
12-18
m18
-24m
24-36
m36
-48m
48-60
m
10th-50th-90th CD4 cell counts/ul
No cytoreduction, n=25 With cytoreduction, n=26CD
4 c
ell/u
l
Months post TCD MM related BMT for SCID
1
10
100
1000
100000-3
m3-6
m6-9
m9-1
2m12
-18m
18-24
m24
-36m
36-48
m48
-60m
0-3m
3-6m
6-9m
9-12m
12-18
m18
-24m
24-36
m36
-48m
48-60
m
10th-50th-90th CD8 cell counts/ul
No cytoreduction, n=25 With cytoreduction, n=26
CD
8 c
ell/u
l
Months post TCD MM related BMT for SCID
1
10
100
10000-3
m3-6
m6-9
m9-1
2m12
-18m
18-24
m24
-36m
36-48
m48
-60m
0-3m
3-6m
6-9m
9-12m
12-18
m18
-24m
24-36
m36
-48m
48-60
m
10th-50th-90th CD56 cell counts/ul
No cytoreduction, n=25 With cytoreduction, n=26
CD
56 c
ell/u
l
Months post TCD MM related BMT for SCID
1
10
100
1000
100000-3
m3-6
m6-9
m9-1
2m12
-18m
18-24
m24
-36m
36-48
m48
-60m
0-3m
3-6m
6-9m
9-12m
12-18
m18
-24m
24-36
m36
-48m
48-60
m
10th-50th-90th CD20 cell counts/ul
No cytoreduction, n=25 With cytoreduction, n=26
CD
20 c
ell/u
l
Months post TCD MM related BMT for SCID
10th-50th-90th percentile of serum IgG post Mis-matched TCD BMT for SCID: Donor B versus Host B
cells
0
500
1000
1500
20000-
6m
6-12
m
12-1
8m
18-2
4m
24-3
6m
36-4
8m
48-6
0m
0-6m
6-12
m
12-1
8m
18-2
4m
24-3
6m
36-4
8m
48-6
0m
60-7
2m
Donor B cells Host B cells
10th-50th-90th percentile of serum IgA post Mis-matched TCD BMT for SCID: Donor B versus Host B
cells
0
50
100
150
200
250
300
350
0-6m
6-12
m
12-1
8m
18-2
4m
24-3
6m
36-4
8m
48-6
0m
60-7
2m
0-6m
6-12
m
12-1
8m
18-2
4m
24-3
6m
36-4
8m
48-6
0m
60-7
2m
Donor B cells Host B cells
10th-50th-90th percentile of serum IgMpost Mis-matched TCD BMT for SCID: Donor B versus Host B
cells
0
50
100
150
200
250
300
0-6m
6-12
m
12-1
8m
18-2
4m
24-3
6m
36-4
8m
48-6
0m
0-6m
6-12
m
12-1
8m
18-2
4m
24-3
6m
36-4
8m
48-6
0m
60-7
2m
Donor B cells Host B cells
Comparison of the percentage of children with PHA greater or equal to 80% of the lower limit of normal post SBA- E- BMT for SCID: With OR Without pre-transplant
cytoreduction
0
20
40
60
80
1000-
6m
6-12
m
12-1
8m
18-2
4m
24-3
6m
36-4
8m
48-6
0m
60-7
2m
>72
M
Perc
enta
ge w
ith
norm
al P
HA
RESPONSES TO PHACD4+ CD45RA+
cells
/mcl
1
10
100
1000
MYELOABLATIVECONDITIONING
NONE
0
20
40
60
80
100
% N
OR
MA
L
MYELOABLATIVECONDITIONING
NONE
ANALYSIS OF T-CELL RECONSTITUTION 10+ YRS POST TRANSPLANT
N=112-811
CAUSES OF DEATH
EARLY LATE
Pre or WithoutEngraftment
PostEngraftment
PostT cell Reconstitution
N 9 5 6
CMV hepatitis or CMV Encelphalitis 3 Viral Pneumonia** 1 COPD 4
Viral Pneumonia* 4 Sepsis 1 Chronic Hepatitis 1
Toxicity (20 BMT) 1 Toxicity 2 Metabolic Seizures 1
EBV LPD GVHD 1
LATE COMPLICATIONS IN T-CELL RECONSTITUTED HOSTS
Cytoreduced Non-cytoreduced
TOTAL PATIENTS 25 28
Affected Patients 2 ( 8%) 11 (37%)
→ COPD + Hepatitis + Nephritis 0 1
→ Chronic Obstructive Lung Disease 0 7
→ Chronic Non-Viral Hepatitis 0 1
→ Interstitial Nephritis 0 2
→ Polymyopathy 2 0
Persistent Infections 0 6
Warts 5
Molluscum 1
CONDITIONING
NO YES
Outcome of patients with X-linked SCID, n=18
Cause of Infection
Alive COD
(-) Cytoreduction, n=10Without infection
N 10/10152 (63-263m+)
NA
(-)Cytoreduction, n=6With antecedent infection
RSV IP, n=1PCP, n=2Measles, n=1Paraflu 3, n=1IP, unk, n= 1
2/6
4.7m+129.6m+
MeaslesParafluGraft failureLate Liver failure @70 months
(+) Cytoreduction, n=2With antecedentinfection
RSV, n=1 Cryptosporidium , n=1
2/219.7m+144.5m+
NA
Function of surviving patients with X-linked SCID, n=14*
Function
B cell NK
ACHIEVED NORMAL
T cell function
Late Decline in TCell function
(-) Cytoreduction, n=13Without infection
0 3/14 13/13 6/13
(+) Cytoreduction, n=2 2 /2 2/2 2/2 0/2
* 1 patient TETE (4 m+), 1 late death @ 70m
Kinetics of PHA response (% normal) in SCID patients who did notdevelop secondary T cell deficiency post TCD MM BMT
0
20
40
60
80
100
0-6m
6-12m
12-1
8m18
-24m
24-3
6m36
-48m
48-6
0m60
-72m
72-8
4m84
-108m
108-
132m
132-
156m
156-
168m
Pt5, X-linkedPt6, X-linkedPt7, X-linkedPt8, X-link
Months post SBA- E- MM-Related BMT: No cytoreduction
Kinetics of PHA response (% normal) in SCID patients who developed secondary T cell deficiency post TCD MM BMT
0
20
40
60
80
100
0-6m
6-12m
12-1
8m18
-24m
24-3
6m36
-48m
48-6
0m60
-72m
72-8
4m84
-108m
108-
132m
132-
156m
Pt1, Aut RPt2, X-linkedPt 3 X-linkedPt 4, X-linked
Months post SBA- E- MM-Related BMT: No cytoreduction
HLA Haplotype Disparate SBA-E- T cell Depleted Marrow Grafts
No Cytoreduction Myeloablative Cytoreduction
T cell chimerism + +T cell function + +B cell chimerism Rare Consistent mixed or full
chimerismAntibody production Rare ConsistentNK cell function Persistent deficiency Consistent normal function
Late reductions in thymic output and new T cell production >80% 10%
Late development of “autoimmune”nephritis and hepatitis 5-10% 0%
HPV infections Common RareViral hepatitis Significant risk Rare
Survival at 15 Year by Primary Conditioining and 2nd BMT Mismatched T-Depleted BMT for SCID
0
0.2
0.4
0.6
0.8
1
0 3 6 9 12 15
Time Post Transplant (Years)
Prop
ortio
n
BMT w ith Primary Conditioning, 78.14% n=30
BMT w ithout Primary Conditioning and no 2nd BMT, 73.43% n=23
BMT w ithour Primary Conditioning and 2nd BMT, 59.26% n=15
Hematopoietic Cell Transplant
With Myeloablation Without Myeloablation
Marrow Pool of Donor Progenitors
Marrow Pool of Donor Progenitors
NK Precursors
NK Cells
B Cell Precursors
B Cells
Early T cell Reconstitution with Late Exhaustion
Early and Sustained Late T cell Reconstitution
Sustained influx of lymphoid progenitors
Host thymus
Immediate Thymic Repopulation
X
The Importance of Sustained Engraftment of a Pool of Donor-Derived Self-Renewing
Hematopoietic Progenitor Cells
1. Engraftment of donor NK cells and reconstitution of NK cell function
2. Engraftment of donor B cells for reconstitution of humoral immunity
3. Maintenance of an adequate pool of thymic precursors to sustain T cell reconstitution
4. Maintenance of thymic constituents critical for positive selection of antigen-reactive cells and negative selection against auto-reactive T cells?