Hematopoietic Stem Cell Transplantation for Fanconi Anemia John E. Wagner, M.D. Blood and Marrow Transplant Program University of Minnesota Cell Therapy for Pediatric Diseases NHLBI PACT Workshop 14‐15 September 2011 Classic Manifestations of FA Short stature Renal agenesis Radial ray defects Marrow failure
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Hematopoietic Stem Cell Transplantation for Fanconi Anemia
John E. Wagner, M.D.
Blood and Marrow Transplant Program University of Minnesota
Cell Therapy for Pediatric Diseases NHLBI PACT Workshop 14‐15 September 2011
Classic Manifestations of FA
Short stature Renal agenesis
Radial ray defects Marrow failure
Fanconi Anemia
• >14 genes identified
• Defect in DNA repair pathway
• Defined natural history (phenotype/genotype correlations but ethnic and racial variations)
• Broad impact (model for understanding DNA repair 100
120 Revertant FA BM
ntrol
understanding DNA repair, cancer biology, stem cell survival, organogenesis)
• Selective growth advantage of normal HSC 0
20
40
60
80
100
0 5 10 25 50 100
FA BM
Normal BM
MMC
CFC
relative to con
Fanconi AnemiaPredisposition to Marrow Failure and Cancer
l
Median age of diagnosis
Most early deaths are due to BM failure or leukemia
Most late
of diagnosis is 7 years
Blood 2003; 101:1249
Most late deaths are due to solid tumor
PROBABILITY OF SURVIVAL AFTER ALLOGENEIC TRANSPLANTS FOR FANCONI ANEMIA
BY DONOR TYPE AND AGE, 1994-1999IBMTR /ABMTR Newsletter 1 Feb 2002
State of BMT for FA in 1995
BY DONOR TYPE AND AGE, 1994 1999R
OB
AB
ILIT
Y, %
100
40
60
80HLA-identical sibling, 10y (N = 109)
Unrelated, 10y (N = 36)
HLA-identical sibling, 10y (N = 100)
IBMTR /ABMTR Newsletter 1 Feb 2002P
R
0
20
0
YEARS
1 2 3 4 6
P = 0.0001
5
Unrelated, 10y (N 36)
Unrelated, 10y (N = 58)
Sibling Donor Unrelated Donor
Reasons for Poor Outcomes in Patients with an Unrelated Donor
Sibling Donor Unrelated Donor
HLA matched
Earlier treatment
Cy 20 TAI 500 cGy
HLA mismatched
Late treatment
Cy 40 TBI >450 cGy
Good Outcome
Poor Outcome
Identify potential solutions
Setting the Agenda Fanconi Anemia Research Fund
Identify potential solutions
Have an HLA matched donorDevelopment of Unrelated Donor Registry
PGD/IVF ‘Savior Sibling’Sa o S b g
Fund the work
Identification of Genes Gene Therapy Trials BMT Trials
ObservationsDeliberate Conception 1985‐1995
HLA matched (n=12)
Pregnancies (n=77)
Normal (n=63)
( )
19.04%
Elective abortion (n=3)7.9%
Affected (n=14) Elective abortion (n=10)
71.4%
Auerbach AD, Blood Cells 1994
Umbilical Cord Blood Transplant New Source of HSC
UCB collected in North Carolina
Tested at Rockefeller, Indiana University and Baylor
Shipped to Paris
Broxmeyer et al.
ObservationsDeliberate Conception 1985‐1995
HLA matched (n=12)
Pregnancies (n=77)
Normal (n=63)
( )
19.04%
Elective abortion (n=3)7.9%
Affected (n=14) Elective abortion (n=10)
71.4%
Auerbach AD, Blood Cells 1994
PGD to prevent disease and save the life of an existing child
PGD for
zona pellucida
PGD for mutation
PGD for HLA
To eliminate risk of genetic disease
To create an HLA identical stem cell donor
blastomeres
Embryo 4
on
0 8
1.0n=14
Fanconi AnemiaSurvival after HLA matched UCBT
mulative proportio
0 2
0.4
0.6
0.8
40% success rate Maternal age factor
Cum
Months after HSCT
0.0
0.2
0 2 4 6 8 10 12 14 16 18 20 22 24
October 2000
on
0 8
1.0n=28
Fanconi Anemia/Aplasia Transplant Outcomes after HLA matched BMT/UCBT
mulative proportio
0 2
0.4
0.6
0.8BM CD34 selected (n=16) UCB (n=12)*
• No graft failure
• No GVHD
Conditioning‐FLU 35 mg/m2 x 4 ‐CY 5 mg/kg x 4
Cum
Months after HSCT
0.0
0.2
0 2 4 6 8 10 12 14 16 18 20 22 24
• No TRMg/ g
‐CsA for 60 days
Unrelated Donor HSCT for FA Tackling Problems
Poor engraftment
Intolerance to GVHD and/or its treatment
High risk of infection
Cy 10 mg/kg/day x 4 days
TBI 450 cGy
CsAT cell depleted
BM
GVHD low (18%) Graft failure high (35%) Survival better (23%)
Unrelated Donor HSCT for FA Tackling Problems
Series of 20‐25 patient trials
Add TCD
Add fludarabine GF solved
GVHD solved
Add thymic shielding
TBI dose de escalation
Reduced OI
? Too early
Radiation Therapy pyThymic Shielding
Left Lung
Total (Ant+PostTotal (Ant+Post))
Posterior beamPosterior beam
%)
%)
Right LungLeft LungLeft Lung
Anterior beamAnterior beam
DistanceDistance
Dose(%
Dose(%
Maximum dose
Mean dose
Thymus
15% (45 cGy)
17% (51 cGy)
Thymic Shielding Reduces Risk of Infections
Total # I f ti
# Bacterial I f ti
# Viral I f ti
# Fungal I f tiInfections per
PatientInfections per
PatientInfections per
PatientInfections per
Patient
TBI 450 including Thymus
2.93 1.58 0.86 0.49
TBI 450 with Thymic h ld
0.56 0.25 0.19 0.13Shielding
TBI 300 with Thymic Shielding
0.11 0.52 0.33 0.14
P value P < 0.01 P < 0.01 P < 0.01 P < 0.01
Small Patient TrialsImpact on Survival
n
1.0 2006 ‐ FLU/CY/ATG/TBI 300/150 TS 89%I
I
I I IIIII I I I I IIIII
mulative Proportion
0.4
0.6
0.8
1999‐2003 FLU/CY/TBI/ATG, TCD 67%
2003‐2006 FLU/CY/ATG/450TBI TS 75%
I I I IIIIIIIIIII
I I I I I II I I
Years
Cum
0.0
0.2
0 1 2 3 4 5
1995‐1999 CY/TBI, TCD 23%
TBI 450
TBI 300
TBI 150
D/C
Unrelated Donor HSCTFor FA
CY10 CY10 CY10 CY10
HCT
TCD BM
UCB
FLU 35 FLU 35 FLU 35 FLU 35
ATG ATG ATG ATG ATG
/
Thym
ic Shielding
G‐CSF (ANC 2500)
CSA (Day 180)
(Day ‐5 to 15)MP
‐6 ‐5 ‐4 ‐3 ‐2 ‐1 0 1 2 3
Good Engraftment Despite Thymic Shielding and Reduced Dose TBI
450 no TS 95%300/150 TS 95%1.0
ulative Proportion
450 TS 92%
P=0.740.4
0.6
0.8
I
III
Days
Cumu
0.0
0.2
0 7 14 21 28 35 42
Median 11 days (9‐30)
Low Risk of Acute GVHD with TCD
Low Risk Chronic GVHD
e
1.0
P=0.15
450 TS 19%300/150 TS 0%umulative Inciden
ce
0.4
0.6
0.8
450 TS 8%450 no TS 19%300/150 TS 0%
Months after HCT
Cu
0.0
0.2
0 2 4 6 8 10 12
University of Minnesota Unrelated HSCT for FA
on
1.0I I I I
I I I
Patients 10 yrs old or less 100% (n=10)
umulative Proportio
All patients including adults 83% (55‐94%) (n=28)
0.4
0.6
0.8I I I I II I I I I II
Years
Cu
0.0
0.2
0 3 6 9
CY10 CY10 CY10 CY10
HCT
TCD BM
TBI 300
Unrelated Donor HSCTFor FA
ding
‐6 ‐5 ‐4 ‐3 ‐2 ‐1 0 1 2 3
UCB
(D 5 t 15)MP
FLU 35 FLU 35 FLU 35 FLU 35
ATG ATG ATG ATG ATG
MMF d 0 t 35
Thym
ic Shield
G‐CSF (ANC 2500)
CSA (Day 180)
(Day ‐5 to 15)MP
Quality of Life Risk of avascular necrosis Risk of infection Need for insulin
MMF days 0 to 35
Lessons Learned
• Embed research and clinical care, clearly
GeneralEmbed research and clinical care, clearly demarcating the two
• Educate the FDA reviewers about the disease and its severity
• Enlist outside consultants to insure objectivity j yabout patient eligibility and responses to therapy
• Develop a roadmap, making one change at a time
Lessons Learned
Disease specificUtili ti t d• Utilize patient advocacy groups
‐ to help direct questions next questions
‐ TCD even for those with HLA genotypic identical donors