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234835.ppt
1. Introduction/Overview
Specific Diseases
Alternative Stem Cell Transplantation
Supportive Measures
Overview of Blood and Marrow
Transplantation
History of BMT
Definitions
AML ALL
Breast cancer
NHL
Rationale
Stem cell sources
MDS
Multiple Myeloma
Hodgkin’s disease
4. HISTORY OF STEM CELL TRANSPLANTATION
Turn of the 20th century, scientists began to
formulate the idea that a small number of cells in
the marrow, referred to as “stem cells”, might be
responsible for the development of all blood cells.
Marrow injury was an important and potentially lethal
side effect of exposure to the atomic bomb or to
industrial accidents in the atomic weapons
industry.
Spurred by the Atomic Energy Commission's and the
military’s concern about the spread of nuclear
technology and weapons, studies of bone marrow
transplantation were initiated.
6. Effects of Spleen Shielding on Mice
After Total Body Irradiation
TBI Dose
(cGy)
700
700
1050
1050
1200
Spleen
Shielding
Yes
No
Yes
No
Yes
Survival
96.3%
0.0%
30.4%
0.0%
0.0%
7. Rationale for High Dose Therapy and
Hematopoietic Stem Cell Transplantation
Increasing
Dose
Treatment Necessary for Cure
Death due to
other organ
toxicity
Death due to
Marrow toxicity
10. TYPES OF STEM CELL TRANSPLANTS
AUTOLOGOUS TRANSPLANTS - Patients
receive their own stem cells.
SYNGENEIC TRANSPLANTS - Patients
receive stem cells from their identical twin.
ALLOGENEIC TRANSPLANTS - Patients
receive stem cells from someone other than
the patient or an identical twin.
11. Potential Stem Cell Sources
Autologous stem cells
HLA-matched related donors
HLA-matched unrelated donors
Haploidentical related donors
Umbilical cord blood
12. Criteria
Tumor with dose response curve
Tumor sensitive to myelosuppressive agents
Purging techniques if marrow is contaminated
with tumor
- Preserve stem cells
- Eradicate tumor
Technique for peripheral stem cell collections
Minimal tumor burden
Marrow ablation
Autologous Bone Marrow
Transplantation
13. Allogeneic Engraftment
With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, T-
and accessories cells) to overcome rejection.
Graft
Stem cell dose
T-cell dose (CD8)
Graft facilitating cells
Stromal stem cells?
Host
Immunosuppression
Preparative regimen
Post-transplant Rx
Disease effects
Sensitization
14. Allogeneic Engraftment
With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, T-
and accessories cells) to overcome rejection.
Graft
Stem cell dose
T-cell dose (CD8)
Graft facilitating cells
Stromal stem cells?
Host
Immunosuppression
Preparative regimen
Post-transplant Rx
Disease effects
Sensitization
15. Engraftment
With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, T-
and accessories cells) to overcome rejection.
Graft
Stem cell dose
T-cell dose (CD8)
Graft facilitating cells
Stromal stem cells?
Host
Immunosuppression
Preparative regimen
Post-transplant Rx
Disease effects
Sensitization
17. HUMAN LEUKOCYTE-ASSOCIATED
(HLA) ANTIGENS
A set of proteins on the surface of their cells.
A set of HLA proteins are inherited equally from
patients.
Chances of having a full match are ~ 1 in 3.
The higher the number of matching HLA
antigens, the greater the chance that the
patient’s body will accept the donor’s stem
cells.
28. Probability of Finding a Six-antigen
HLA Matched Donor
100
1000
10,000
100,000
500,000
1,000,000
0.0%
11.9%
54.2%
90.6%
99.9%
99.9%
0.0%
3.3%
20.7%
60.0%
85.7%
93.7%
Pool Size Japanese North America
Caucasian
30. Cord Blood Transplantation
Advantages Disadvantages
Waste product of
normal deliveries
Readily available
Increased availability
for minorities
Decreased
transmission of
viruses (e.g. CMV)
One unit rescues one
patient/no DLI
Theoretical risk of
genetic disease
transmission
Theoretical risk of
maternal cell
contamination (GVHD)
Efficacy in adults
unknown
31. Haplo-identical HSCT
Advantages Disadvantages
Nearly all patients
have a donor
Share major (e.g.
HLA-C) and minor
hitocompatibility
antigens
Immediate donor
availability
HLA Barriers:
-Graft rejection
-GVHD
-Immune
dysregulation
32. Strategy for Donor Selection
BMT
No
Urgent
Referral
Simultaneous Search URD, BM and UCB
Non-urgent or
Non-malignant
Diagnosis
Yes Yes
UCBT
6/6 HLA-matched BM
Donor Available?
4-6 HLA-matched UCB(s)
Identified with Cell Dose
>1.5 x 107
NC/kg?
33. Choice of Stem Cell Source
Diagnosis
Urgency of transplant
HLA typing
Cell dose available in UC units(s)
Age
Chemo-sensitivity
35. Indications for Blood and Marrow
Transplantation in North America
(2000)
4,500
3,000
2,000
1,000
0
AML Hodgkin
Disease
CML MDS/
Other
Leukemia
CLL
Ovarian
Cancer
Non-
Hodgkin
Lymphoma
Transplants
Allogeneic (Total N=67,000)
Autologous (Total N=11,000)
4,000
2,500
1,500
500
3,500
Non-
Malignant
Disease
ALL
Other
Cancer
Breast
Cancer
Multiple
Myeloma
36. Annual Numbers of Blood and Marrow
Transplants Worldwide
(1970-2000)
40
30
20
10
0
1975 1980 1985 1990 1995 2000
1970
Year
Number
of
Transplants
(Thousands)
Autologous
Allogeneic
37. Advancements in Allogeneic
Stem Cell Transplantation
Alternative donors
Unrelated bone marrow donors
Stored cord blood
Ganciclovir
Hematopoietic growth factors
Blood as a stem cell product
Donor lymphocyte infusions
38. Donor Lymphocyte Infusions
Efficacy varies:
High incidence of GVHD (40-60%)
High correlation of GVHD and response
Optimal dose, frequency and timing
remain undetermined
CML = 50-90%
AML = 25-50%
39. Allogeneic Hematopoietic Stem Cell
Transplantation
The allograft is a
rescue product to
replace the defective
stem cells following
ablation with
cytotoxic therapy.
Main therapeutic
component of an
allogeneic stem cell
transplant is the
“graft vs. leukemia”
effect mediated by T-
cells in the allograft.
Old Paradigm New Paradigm
40. Non-myeloablative Regimens in Allo
SCT
Advantages:
-Decreased acute toxicity
-Application to older and/or morbid patients
-Application to broader spectrum of diseases
Disadvantages:
-Toxicity of the procedure (GVHD)
-Loss/decrease in anti-tumor activity from
cytotoxic chemotherapy/radiation
