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


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


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


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


No cytoreduction, n=25 With cytoreduction, n=26CD

4 c

ell/u

l


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



CD

8 c

ell/u

l


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



CD

56 c

ell/u

l


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



CD

20 c

ell/u

l


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


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


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


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?

the mskcc experience scid_oreilly.pdf · scid defect of 68 consecutive recipients of a parental hla...

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