Download Response to PEG-ADA

Severe Combined
Immunodeficiency Syndrome
• A heterogeneous group of congenital disorders which
results in the absence of antigen-specific T and B cell
responses
 1/50-100, 000 live births
 Newborn screening estimate now 1/30-40,000 live birth
 Athabascan-speaking Native Americans, an incidence of
52/100,000 live births
• Early classification based on presence or absence of
adenosine deaminase and the % and absolute
numbers of T, B, and NK cells
Genetic mutations associated with SCID
Gene
Function
Phenotype
Chromosomal
location
Year
Published
ADA
Purine salvage enzyme
Recycles adenosine and
deoxyadenosine after DNA
breakdown
T, B-, NK+
20q12-13
1972
TCR abn
Signaling through TCR
Tlo, B+,NK+
11q23
g chain
Common g chain
(IL-2,4,6,15,21)
T-,B+, NK-
Xq13
1987
1993
ZAP 70
Tyrosine
Kinase
CD8 def
2q12
1994
Janus kinase- 3
Tyrosine kinase
Signaling through gC
T-, B+, NK-
19p13
1995
RAG1, RAG-2
•Omenn's
syndrome
Recombinase activating
genes
initiation of VDJ
recombination
T-B-NK+
11p13
1996
T+, B-,NK+
IL7-Ra
Cytokine Receptor
T-, B+, NK+
5p13
Artemis
DNA repair enzyme
T-B-NK+
10p
1998
1998
Mutations associated with SCID
Gene
GENE
FUNCTION
Common
Phenotype
Chromosoma
l location
Year
published
CD45
TYROSINE
KINASE
T-,B+,NK low
Chr 1
2000
DNA ligase IV
DNA REPAIR
ENZYME
T(low),B+,
NK+
11q23
2001
IL-2R/IL-15b
subunit
Cytokine receptor
subunit
T (low) B+
NK-
Unk
2001
FOXP3
Mutations
IPEX
T reg
deficiency
Immune
dysfunction
polyendocrinopathy
Enteropathy
X linked
Auto
variants
2001
Adenylate
kinase 2
AK2
Reticular
dysgenesis
mitochondrial
intermembrane
space, stria
vascularis region
of the inner ear
T-B-NK+/Absent
neutrophils
Deafness
1p31–p34
2009
Diagnosis and Outcome of infants identified by newborn Screening
Diagnosis
Evaluation
Treatment
Outcome
Outcome
#1
ADA deficiency
now 17 months old
34 lymphs/ul
PEG ADA
Normal T cell
function
Vaccinated
Successfully
#2
X linked
+ FH
Now 16 months
B+, NK+, T-
TCD HLA-MM
Related BMT
Normal T cell
function
#3
ADA deficiency
Now 16 months old
117 lymphs/ul
85% NK, 15% B
PEG ADA
Normal T cell
function
#4
Normal
NL phenotype
NL T cell func
NL B cell function
#5
Transient
T lymphopenia
Now 9.5 months old
CD3-233/ul
T cell numbers
Normalized
NL T cell function
Vaccinated
Successfully
IgG3 deficient
#6
T lymphopenia
NL ADA, IL-7R, nl
NL CD3 d, e
Now almost 9m
CD3:741/ul, inc
B
CD4:613/ul
CD8:117/ul
T cell numbers
Increasing but
not normal
NL T cell function
Vaccinated
Successfully
#7
X linked
Now 4 months old
B+, NK+, T-
TCD HLA –MM
RelBMT
3+ m, well
No GVHD
T cells coming in
#8
Likely X-linked
NL ADA, PNP
ALC 1450, B
1450/ul
No T, NK 29/ul
Being HLA typed
3 weeks old
Vaccinated
Successfully
Pre HCT
Laboratory Evaluation
Lymphoid phenotype
PHA, MLC, NK function
ADA and PNP levels
Immunoglobulin levels
HIV Ab parents, HIV PCR child
HLA Class I and Class II expression
+/- phenotyping for CD127 (IL-7R)or
CD132 (IL-2g chain) if consistent
phenotype
Response to PEG-ADA
• 20% show no response
• Majority see T cell immune response in
the short term but it wanes with time
• B cell immunity, 50% will need continued
IVIG
– B cell numbers increase within a few weeks of
therapy
– T cell numbers may require several months to
increase
RESPONSE TO PEG-ADA in two infants identified by NBS
#CD56
#CD3
#CD4
#CD56
#CD8
#CD3
500
600
400
500
300
400
Cells/ul
Cells/ul
600
200
#CD4
#CD8
300
200
100
100
0
0
5
10
0
15
0
Age (months)
5
10
15
Age (months)
#CD19 B cells
#C19 B cells/ul
2500
600
1500
Cells/ul
Cells/ul
2000
1000
400
200
500
0
0
5
10
Age (months)
15
0
0
5
10
Age (months)
15
Response to PEG-ADA
200000
200000
CPM
150000
CPM
250000
PHA Response
Patient #1
LLN:>109,000
100000
50000
150000
PHA response
Patient #2
LLN:
>109,000
100000
50000
0
0
0
5
10
15
0
5
Diph
Pert
Pre
0.81
1.01
6
Post
3.43
1.39
403
15
Age (months)
Age (months)
Tet
10
HIB
PRE
1(0.6)3(1.40)4(0.0)14(3.4)19(2.0)23(0.9)6B(1.20) 7F(1.3)18c(0.90)
POST PCV13x3
1(8.1)3(>37.6)4(6.5)14(2.1)19(7.4)23(3.3)6B(11.8)7F(33.9)18C(12.3
)
Tet
Diph
Pert
HIB
Pre
1.21
0.6
5
1.61
Post
6.79
>2.5
37
>9
PRE
1(0.8)3(>37.5)4(0.5)14(2.1)19(1.2)23(0.6)6B(0.7)7F(4.4)18c(0.6)
POST PCV13x3
1(9.3)3(34.4)4(4)14(1.6)19(6.4)23(1.3)6B(3.9)7F(18.1)18c(6.6)
Results of HCT for ADA deficiency
Publication
Eur
Experience*
MSKCC
Ulm, Munich
HLA MSIB
81%, n=19
none
100%, n=7
81-100%
*50% survivors had neurologic deficits
Alternative
donor
29%, n=26
50%, n=8
63%, n=8
29%-63%
Newborn Screening
 Allows early identification and treatment of affected infants



EFS if HCT <2 months of age: 90-100%
Currently how well young infants tolerate cytoreduction is
unknown
How much cytoreduction to ensure B cell engraftment unknown
NBS also uncovers infants who may have transient
lymphopenia or immune defects that previously were
unrecognized and may or may be associated with an
increased risk of infection.
Need to determine best way to inform parents
Current literature needs to be translated into multiple languages
Available literature for parents is either too simplistic or too
complicated
Longitudinal lymphoid phenotype of female child
with low-absent TRECS on newborn screen
Patient # 1
Serum Ig levels
Total lymphs
#CD3
#CD4
#CD8
#CD19
#CD56
4000
3000
2000
600
IgG
IgA
IgM
400
mg/dl
Absolute number/ul
5000
200
1000
0
0
0
2
4
6
8
10
0
Months of age
2
4
6
8
10
Months of age
Percentage CD4+CD45RA+ cells
Absolute numbers of CD4+ CD45RA+ cells
1.0
1500
Normal
TRECS
cells/ul
Percentage
0.8
0.6
0.4
1000
No
TRECS
500
0.2
0.0
0
0
2
4
Age (months)
6
0
2
4
Age (months)
6
Lymphoid phenotype and function
%CD4/
CD45RA
Age
ALC
CD3
CD4
CD8
CD19
CD56
2
months
1750
228
140
53
735
770
2.5
months
1966
550
354
177
1219
216
0.33
3
months
2674
856
508
321
1444
508
0.47
3.9
months
2700
1161
675
459
1269
351
0.72
5. 1
months
4090
2536
1594
900
1268
286
0.79
PHA
OKT3
160,143
13, 478
189, 056
Longitudinal immune phenotype and function of female infant
with low but detectable TRECs on newborn screen
1000
900
800
700
600
500
400
300
200
100
0
CD19 Bcells
#CD3
#CD4
#CD8
#CD56
1500
1250
Cells/ul
Cells/ul
T Lymphopenia, normal function
NL antibody response
1000
750
500
250
0
0
1
2
3
4
0
5
1
Age at
test
PHA
LLN 109, 576
OKT3
LLN 3, 715
Candida
LLN: 6624
1.9 m
262881
101032
3283
2.6m
144050
77453
4.2m
100222
5.7m
185539
2
3
4
5
Age (months)
Age (months)
Tetanus Toxoid
LLN:2417
Vaccine Responses
1050
31749
4673
6614
+ Response to Tetanus,
Pertussis, Diphtheria
PCV13, HIB
Why do children with
SCID ever need
cytoreduction
To ensure donor B cell
engraftment
To prevent graft rejection
in patients with NK activity
via KIR pathways
In pts with ADA
deficiency-to ensure 100%
donor chimerism including
red cell lineage
To prevent T cell
mediated graft rejection in
those with PHA >5% LLN
Effect of pre-HCT NK function on
engraftment following TCD MMrelated SBA- E- BMT
in the absence of cytoreduction
PRE
HCT
Engrafted
NK
function
Failed to
engraft
Absent
14/14
0/14
Present
1/8
7/8
CHI-SQUARE=17.9, p <.001
Results of unmodified HLA-matched related BMT
• Matched sibling transplant remains the treatment of choice
• Cytoreduction or GVHD prophylaxis generally unnecessary
• European Experience 1968-1999: 81%, n=104,
– ADA def: 81%, Reticular Dysgenesis: 75%-HLA matched BMT
• Single Center
– MSKCC: 1971-2011, 87.5% survival, n=16
– Hopital Necker-Enfants Malades 1971-92, 80%
survival, n=30
– Univ of Ulm: 81% survival, n=21
– DUMC: 1982-98, 100% survival, n=12
– Univ of Brescia: >80%, n=35
T and B cell function following unmodified HLAmatched BMT for SCID
 Normal T cell numbers
rapidly restored 2-4
weeks
2000
Pt #1
Pt #2
Pt #3
1500
 Normal T cell mitogen
and specific antigen
responses restored
Pt #4
1000
500
 B cell function returns by
one year post transplant
0
pre HCT
1-29d
30-59d
60-89d
What about patients who lack HLA matched sibling
donor
TCD HLA Mismatched BMT
Depending on efficiency of T cell depletion
Current outcomes: 70-80%, and if HCT <2 months:
90-100%
Low incidence of GVHD
Parent readily available
Probability of Overall Survival after Unrelated
Donor Transplants for SCID, 1990-2004, n=200
Probability
1.0
Overall survival, 60%
(95% CI 52-67) @ 5 years
0.8
0.6
0.4
No significant advantage over parental T cell depleted HLA
non-identical marrow grafts when comparable preparative
regimens are used
0.2
Potential risk of infectious complications due to time needed
to procure a donor
Increased Risk of GVHD
0.0
0
1
2
3
Years
4
5
Probability of Overall Survival after Unrelated
Donor Transplants for SCID, 1990-2004, n=200
Probability
1.0
Overall survival, 60%
(95% CI 52-67) @ 5 years
0.8
0.6
0.4
No significant advantage over parental T cell depleted HLA
non-identical marrow grafts when comparable preparative
regimens are used
0.2
Potential risk of infectious complications due to time needed
to procure a donor
Increased Risk of GVHD
0.0
0
1
2
3
Years
4
5
Probability of Overall Survival after Unrelated
Donor Cord Blood Transplants for SCID, 19902005, n=76, CIBMTR
Probability of survival
1.0
0.8
Overall survival, 57% (95% CI 44-69) @ 5 years
0.6
Immediately available unlike MUD HCT
Viral naïve, CMV seronegative
Less acute and chronic GVHD despite 1-2 Ag MM
No clear advantage over HLA MM-Rel HCT
Higher risk of GHVD, appox 25% aGVHD, 13% chronic
0.4
0.2
0.0
0
1
2
3
Years Post HCT
CIBMTR data, 2007
4
5
Immune Function
• 50% of children have normal T cell
function in the first 6 months post BMT
• 80% have normal T cell function by 6 to
12 months post BMT
• However, without cytoreduction, lack of
donor B cell engraftment, IVIG
dependent
Recovery of T cells post SBA- E- parental
BMT for SCID
10000
1000
100
SCID, with cytoreduction
10
SCID, without cytoreduction
1
Months post Mis-related parental TCD BMT for SCID
Recovery of CD4+
T cells post SBA- E- parental BMT for SCID
2000
SCID, with cytoreduction
1600
SCID, without cytoreduction
1200
800
400
0
Months post Mis-related parental TCD BMT for SCID
Numbers of circulating naive CD4+ T cells
post HCT For SCID
CD4+ RA+ T cells per µl
800
700
600
500
400
300
200
100
0
HLA MATCHED SIBLING
HLA MM RELATED
No cytoreduction
HLA MM RELATED
With cytoreduction
Comparison of the percentage of children with normal
PHA post SBA- E- BMT for SCID: With and Without pretransplant cytoreduction
100
80
60
40
20
0
Median serum IgG Levels post Mis-matched TCD BMT for
SCID
1200
1000
CYTO
NON-CYTO
800
600
400
200
0
0-6M
6-12M
12-18M
18-24M
24-36M
36-48M
Median serum IgA Levels
post Mis-matched TCD BMT for SCID
100
CYTO
NON-CYTO
50
0
0-6m
6-12m
12-18m
18-24m
24-36m
36-48m
Conclusions and Future directions
 The majority of children with SCID can be cured by a HCT
providing it is performed early
 Primary immunodeficiency Treatment Consortium (PIDTC)
 Retrospective study to determine variables associated with
outcome
 Prospective study to determine outcome of patients identified
through newborn screening
HCT
Gene therapy
PEG-ADA
 Trial under development to determine lowest amt of
cytoreduction to ensure T and B cell engraftment
 Need to determine the best way to inform parents of NBS which
require further evaluation
 Need to develop ways to promptly direct parents to centers which
can quickly evaluate and treat children with PID