1. Overview of Blood and Marrow Transplantation
Introduction/Overview
Specific Diseases
Alternative Stem Cell Transplantation
Supportive Measures
History of BMT
Definitions
AML ALL
Breast cancer
NHL
Rationale
Stem cell sources
MDS
Multiple Myeloma
Hodgkin’s disease

2. HEMATOPOIETIC STEM CELL DIFFERENTIATION

3. Immunologic Marker Expression
In Hematopoiesis 7
10,19,24,38
33,61 36
13,15,33,38
9,36,41,42,61
13,16,11b
13,16,33
13,14,15,33
9,10,19,20,24,38
2,3,5,7,38
2,3,5,7
Erythrocyte
NK Cell
Platelet
Monocyte
B-Cell
T-Cell
BFU-E
CFU-E
Reticulocyte
Myeloid SC
CFU-Mega
Megakaryocyte
Eosinophil
Basophil
Neutrophil 10
Myeloblast
Promyelocyte
Myelocyte
Pluripotent
Stem Cell
2,3,5,7
19,20,22
11b,16,56
11b,13,14,15,33,36
Monoblast
Promonocyte 56
Lymphoid SC
NK Precursor
B Progenitor
Pre-B
CD34+
T Progenitor
Sub Cortical
Cortical Thymocyte
Medullary
Thymocyte

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.

5. Lethal TBI Syndromes Cerebral Syndrome Intestinal Syndrome
Bone Marrow Syndrome
12,000-1,000,000 cGy
1,200-10,000 cGy
cGy

6. Effects of Spleen Shielding on Mice After Total Body Irradiation
TBI Dose
(cGy)
Spleen
Shielding
Survival
700
1050
1200
Yes No
96.3%
0.0%
30.4%

7. Treatment Necessary for Cure
Rationale for High Dose Therapy and Hematopoietic Stem Cell Transplantation
Death due to
other organ
toxicity
Increasing Dose
Death due to
Marrow toxicity
Treatment Necessary for Cure

8. CONDITIONING (PREPARATIVE) REGIMEN
To suppress the patient’s immune system from rejecting the stem cells.
To eliminate the cancer

9. Stem Cell Sources
Bone Marrow
Blood
Umbilical Cord
Fetal Liver

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. Autologous Bone Marrow Transplantation
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

13. Allogeneic Engraftment
Host
Immunosuppression
Preparative regimen
Post-transplant Rx
Disease effects
Sensitization
Graft
Stem cell dose
T-cell dose (CD8)
Graft facilitating cells
Stromal stem cells?
With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, T-
and accessories cells) to overcome rejection.

14. Allogeneic Engraftment
Host
Immunosuppression
Preparative regimen
Post-transplant Rx
Disease effects
Sensitization
Graft
Stem cell dose
T-cell dose (CD8)
Graft facilitating cells
Stromal stem cells?
With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, T-
and accessories cells) to overcome rejection.

15. Engraftment Host Graft Immunosuppression Preparative regimen
Post-transplant Rx
Disease effects
Sensitization
Graft
Stem cell dose
T-cell dose (CD8)
Graft facilitating cells
Stromal stem cells?
With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, T-
and accessories cells) to overcome rejection.

16. Graph Rejection/
GVHD
Recurrent
Disease

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.

18. HUMAN LEUKOCYTE ANTIGEN INHERRITANCE

19. IDENTIFICATION OF A RELATED ALLOGENEIC DONOR
Identical Twin < 1%
HLA-matched Sibling
6 antigen %
5 antigen %
4 antigen %
3 antigen > 90%

20. Stem Cell Source Allogeneic Autologous Donor Availability
Tumor Content
GVHD/GVL
Tx-related Mortality
Limited
None
Possible
10-40%
Majority
Possible
None
0-10%

21. Alternatives to HLA-matched Related Donors
HLA-matched unrelated donors
Cord Blood Transplantation
-Related
-Unrelated
HLA-mismatched related Donors
(Haplo-identical)
(Autologous stem cell transplantation)

22. Stem Cell Source Donor Availablity Tumor Content GVHD/GVL
Tx-related Mortality
Allogeneic
Limited
None
Possible
10-40%
Autologous
Majority
0-10%

23. Advancements in Allogeneic Stem Cell Transplantation
Alternative donors
- Unrelated bone marrow donors
- Stored cord blood
Ganciclovir
Hematopoietic growth factors
Blood as stem cell product
Donor lymphocyte infusions

24. Stem Cell Donor Availability
HLA-matched relative
Unrelated donor
Cord blood
HLA-mismatched relative
25-30%
10-40%
50%
10%
90%
1 Ag
2 Ag
3 Ag

25. Alternatives to HLA-matched
Related Donors
HLA-matched unrelated donors
Cord blood transplantation
- Related
- Unrelated
HLA-mismatched related donors
(Haplo-identical)
Autologous stem cell transplantation

26. The NMDP Network 98 Donor Center (8 foreign) Coordinating Center
Minneapolis, MN
114
Collection
Centers
(15 foreign)
112
Transplant
Centers
(23 foreign)
ASCO 1998

27. Volunteer Marrow Donors40
Total Donors
3,134,601 30
Volunteers in Registry
(Millions) 20
Fully Typed
Donors 10 89 90 91 92 93 94 88 95 96 97 98
Year
ASCO 1998

28. Probability of Finding a Six-antigen HLA Matched Donor
North America Caucasian
Pool Size
Japanese
100
1000
10,000
100,000
500,000
1,000,000
0.0%
11.9%
54.2%
90.6%
99.9%
0.0%
3.3%
20.7%
60.0%
85.7%
93.7%

29. DR Typing Confirmatory Typing Work-Up Transplant Formal Search
Preliminary Search
1.6%
15.8%
20.2%
43.5%
54.7%
7.2%
2.1%
25.6%
Beatty et al., 1995

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
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

34. Diseases Treated by Bone Marrow Transplantation
Aplastic anemia
Thalassemia
Sickle cell anemia
Immunodeficiency disorders
Acute myelogenous leukemia
Myelodysplastic syndrome
Multiple myeloma
Acute lymphocytic leukemia
Chronic myelogenous leukemia
Chronic lymphocytic leukemia
Non-Hodgkin’s lymphoma
Hodgkin’s disease
Armitage, NEJM 1994

35. Indications for Blood and Marrow Transplantation in North America
(2000)
4,500
4,000
Allogeneic (Total N=67,000)
Autologous (Total N=11,000)
3,500
3,000
2,500
Transplants
2,000
1,500
1,000
500
Non-
Hodgkin
Lymphoma
AML
Hodgkin
Disease
CML
MDS/
Other
Leukemia
CLL
Multiple
Myeloma
Breast
Cancer
Other
Cancer
ALL
Non-
Malignant
Disease
Ovarian
Cancer

36. Annual Numbers of Blood and Marrow Transplants Worldwide
( ) 40 30
Autologous
Number of Transplants
(Thousands) 20 10
Allogeneic
1970
1975
1980
1985
1990
1995
2000
Year

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
Old Paradigm
New Paradigm
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.

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

41. Non-myeloablative Hematopoietic
Cell Transplant
± DLI
HSCT A B AL
Recipient
Donor
Mixed
Chimera
Complete
Host
Preparative Regimen

42. CLINICAL COURSE ON ABP1 (CC 00-C-0119)

43. Hematopoetic Stem Cell Transplantation for Auto-immune Diseases
Multiple Sclerosis
Rheumatoid Arthritis
Scleroderma

44. ETIB RESEARCH HEMATOPOIETIC STEM CELL TRANSPLANTATION
Strategy Tactic
 Rejection Immune-depleting chemo
Tc2 cells
GVHD Th2 cells
GVL Tc2 cells
Id vaccines
Immune reconstitution Cytokines (IL-7)

45. “Diseases desperate grown By disparate appliance Are reliev’d,
Or not at all”
After Shakespeare