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10/24/2011
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Stem CellTransplantation for
Severe Aplastic Anemia
Claudio Anasetti, MD
Professor of Oncology and Medicine
Chair, Blood and Marrow Transplant Dpt
Moffitt Cancer Center
Indications for allogeneic hematopoietic stem cell transplantation in North America
2008
0
500
1,000
1,500
2,000
2,500
3,000
AML ALL MDS/MPS NHL Aplastic
Anemia
CML Multiple
Myeloma
HD Other
Leuk
Other
Cancer
Non-
Malig
Disease
Related Donor (n=3,282)
Unrelated Donor (n=3,389)
SUM10_13.ppt
Slide 11
Num
ber
of
Tra
nspla
nts
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Why Stem Cell Transplantation?
Replaces dysfunctional marrow Myelodysplastic Syndromes
Aplastic anemia
Intense chemotherapy Where standard therapy is insufficient
Relapse risk is high Lymphoma
Leukemias
Myeloma
Immune therapy against the cancer
What is the Bone Marrow?
Central portion of bone
Contains basic blood elements
In adults, marrow is replaced by fat
in long bones
In hips, sternum, ribs and skull are rich of marrow
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The production of blood
B-CellT-CellMyeloid Progenitor
Progenitors
Erythrocytes
Thrombocytes
Granulocytes,Monocytes
Stem Cells
Types of Transplants
Allogeneic (from another person)
Tissue Type Matched
Related
Unrelated
Tissue Type Mismatched
Unrelated
Cord
Syngenic – identical twin
Autologous (from yourself)
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Timing of Transplant Consultation for Severe Aplastic Anemia (SAA)
At diagnosis
Sibling Transplant outcome:Second line therapy worse than first line therapy
British Journal of Haematology 135: 693-696, 2006
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Timely Referral Affects Survival
Early referral is the single most important
step that can affect survival Lee, et al. Blood 2007
Transplantation Process
Minimize sensitization
Tissue typing
Donor Search
Evaluation
Conditioning therapy
Transplantation
Engraftment
Recovery
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Donor Search
We look for a genetic match
Not your blood type!
Human Leukocyte Antigens
Typing blood or buccal swab
Chance of match
1 in 4 if sibling
1 in 1,000 if unrelated
HLA inheritance
A B DR
a
b
Motherc
d
Father
25%
25%
25%
25%
a
a
b
b
c
c
d
dPossible
Offspring
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Probability of finding an HLA-A, B, C, DRB1 matched donor
p=<0.0000
Total 8/8 7/8 none
Caucasians 89% 62% 27% 11%
Hispanics 77% 34% 43% 23%
African-
Americans
64% 15% 48% 37%
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Total time to transplant
% at risk
Median days
[95% CI]
Search to first donor 85% 20 [11-59]
First donor to back-up donor
34% 8 [3-85]
Donor to transplant 48% 81 [45-199]
Growth in Unrelated Transplants
Unrelated transplant is growing in nearly all diseases for which transplant is indicated
-
200
400
600
800
1,000
1,200
AML ALL Non-Malignant MDS NHL CML
NMDP Transplant Recipients by Diagnosis
2001
2003
2005
2007
National Marrow Donor Program® © 2008
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Pre-transplant Evaluation Medical Assessment
Disease status, assess for Fanconi, Dyskeratosis, PNH, MDS…
Organ function Infectious status by transplant physician
psychologist social workerdentist
Education of the recipient and family
Transplantation Procedure
day 0
Anti-rejection Drugs
ConditioningTherapy
Stem
Cells
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Conditioning Therapy
Suppressive drugs to prevent rejection
SAA – none additional
MDS – chemotherapy
Side effects: Low blood counts
Hair loss
Mouth sores
Vomiting
Diarrhea
Death: 0-2%
Effect of Co-Morbidity ScoreOne Year Transplant MortalityBy Conditioning
28%
67%
More intense
14%
19%
36%
% o
f p
ati
en
ts
Months after HCT Months after HCT
Less Intense
Sorror M, et al Blood 106:2912-9.
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Older Patients Eligible
Transplants for patients over age 50 now account for 35% of all NMDP-facilitated transplants
National Marrow Donor Program® © 2008
Sources of Stem Cells
Bone Marrow
Peripheral Blood
Umbilical Cord Blood
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Bone Marrow
Harvest
• 1-2 hour surgery• Anesthesia required• No growth factors
Blood Stem Cell Collection- Apheresis -
Outpatient procedure
4-6 hours
Growth factors given
No sedation
Peripheral veins used
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Umbilical Cord Blood
Obtained from
placenta remnants
Typed and banked
Less GVHD
Stem Cell
Dosage may be an issue
Stem Cell Transplant
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Immune suppressive DrugsAnti-rejection
Tacrolimus
Cyclosporine
Sirolimus
Methotrexate
Mycophenolate
Anti-Thymocyte Globulin
Prednisone
Issues in Transplants
Rejection
Graft Versus Host Disease
Infection
Organ damage
Late effects
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Issues in Transplants
Rejection <1-10%
Graft Versus Host Disease
Organ damage - chemotherapy
Infection
Late Effects
Major impact of Fludarabine and low dose irradiation
Issues in Transplants
Rejection <1%
Graft Versus Host Disease ~50%
Organ damage - chemotherapy
Infection
Late Effects
Modest impact of tacrolimus and ATG, promising sirolimus
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Clinical manifestationsAcute
Skin rash
Nausea, vomiting
Diarrhea
Abdominal cramps
Intestinal bleeding
Hepatitis: AST, ALT elevation
Cholestasis: GGT, AP, Bili elevation
Thomas E, et al. Bone-marrow transplantation.
N Engl J Med. 1975 ;292:832-43 and 895-902.
Stage 1 GVHD of Skin
http://www.gsic.jp/cancer/cc_21/aml/sp/02.html
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Acute GVHD mortality
Overall Grade
% Non-Relapse Mortality
0 15% 5%
I 5% 5%
II 60% 15%
III 15% 60%
IV 5% 95%
Skin Dark or light spots Hardening
Mouth White plaques Thickening Restriction of mouth
opening
Genitalia Vaginal stenosis
Clinical manifestationsChronic
Gastro-Intestina Esophageal stricture
Lung Chronic Asthma
Joints Stiffness or contractures
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Complications
Infections
From immunodeficiency
From glucocorticoid use
Burn syndrome
GI bleeding
Liver failure
Respiratory Failure
Late effects
Sterility
Secondary cancers
Coronary artery disease
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Years
0 2 61 3 4 5
Probability of survival after allogeneic transplant for severe aplastic anemia,
by age and donor type, 1998-2008
HLA-matched sibling, 20 y (N=1,388)
HLA-matched sibling, >20 y (N=1,408)
Unrelated, 20 y (N=562)
Unrelated, >20 y (N=532)
0
20
40
60
80
100
10
30
50
70
90
0
20
40
60
80
100
10
30
50
70
90
Pro
bability o
f Surv
ival, %
P < 0.0001
SUM10_48.ppt
Slide 41
Survival for Severe Aplastic Anemia has improved over time
Locasciulli A et al. Haematologica 2007;92:11-18
Sibling BMT Unrelated BMT IST
Passweg, J. R. et al. Hematology 2010;2010:36-42
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Transplant Conditioning
Cyclophosphamide
Total Body Irradiation
Anti-thymocyte-globulin
Fludarabine
Sib transplant conditioning:ATGAM is marginally beneficial
Champlin et al. Blood 2007, 109:4582-5.
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Maury S et al. Haematologica 2009;94:1312-1315
Sib transplant conditioning:Fludarabine is beneficial in SAA
.
Wagner J E et al. Blood 2007;109:2256-2262
Unrelated transplant conditioning:Fludarabine is beneficial in FA
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Sib conditioning: Cy + FludarabineSurvival of SAA patients by age
Maury S et al. Haematologica 2009;94:1312-1315
Bacigalupo A et al. Haematologica 2010;95:976-982
Unrelated transplant conditioning:Low dose irradiation is beneficial
200 cGy Total Body Irradiation is well tolerated: outpatient, does not cause loss of hair, mouth sores, diarrhea.
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Unrelated transplant outcome:improved survival after 2004
Bacigalupo A et al. Haematologica 2010;95:976-982
Worse outcome with delayed unrelated transplant
Bacigalupo A et al. Haematologica 2010;95:976-982
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GVHD prophylaxis:Improved outcome with Tacrolimus
Yagasaki et al, BBMT 2009, 15: 1603-1608
Stem cell source:Better outcome with Bone Marrow
compared to Blood Stem Cells
Schrezenmeier H et al. Blood 2007;110:1397-1400
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Promising survival in 12 patients with SAA after unrelated cord blood transplantation
Yamamoto H et al. Blood 2011;117:3240-3242
Yoshimi et al, BBMT 2008, 14: 1057-1063
Conditioning before Unrelated Cord Blood
Transplantation for Severe Aplastic Anemia
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Summary (1)
Transplant outcome has improved
with less toxic but more immune suppressive conditioning with less rejection, and with better GVHD
prevention.
Summary (2)
Tissue matched sibling transplants
should be considered for first line therapy in patients with SAA at diagnosis up to age 40 or 50
depending on comorbidities
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Summary (3)
Transplants should be considered for
second line therapy after immune suppression failure in patients over 50 years of age, or patients without a
tissue matched sibling
Summary (4)
Research continues in the area of
GVHD prevention, immune reconstitution, and prevention of late effects.
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Questions
?
