Introduction/Overview History of BMT Rationale Definitions Stem cell sources Specific Diseases AML ALL MDS Breast cancer Multiple Myeloma NHL Hodgkins disease Alternative Stem Cell Transplantation Supportive Measures
Erythrocyte BFU-E
33,61
CFU-E
9,36,41,42,61
Reticulocyte Platelet
Myeloid SC
CFU-Mega
13,15,33,38
Megakaryocyte
13,16,33 13,16,11b
Myeloblast
Promyelocyte
Myelocyte
13,14,15,33
13,14,15,33
NK Cell Lymphoid SC
10,19,24,38
NK Precursor
9,10,19,20,24,38 19,20,22
B Progenitor
7
Pre-B
2,3,5,7,38
B-Cell
2,3,5,7
2,3,5,7
T-Cell
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 militarys concern about the spread of nuclear technology and weapons, studies of bone marrow transplantation were initiated.
Rationale for High Dose Therapy and Hematopoietic Stem Cell Transplantation
Death due to other organ toxicity
Increasing Dose
To suppress the patients immune system from rejecting the stem cells.
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, Tand accessories cells) to overcome rejection.
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, Tand accessories cells) to overcome rejection.
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, Tand accessories cells) to overcome rejection.
Recurrent Disease
Allogeneic Donor Availablity Tumor Content GVHD/GVL Tx-related Mortality Limited None Possible 10-40%
ASCO 1998
30
20
Fully Typed Donors
10
88 89
90 91 92 93 94 Year
95 96 97 98
ASCO 1998
Japanese
0.0% 11.9% 54.2% 90.6% 99.9% 99.9%
Preliminary Search
54.7% 25.6%
Formal Search
43.5%
DR Typing
7.2%
Confirmatory Typing
20.2%
Confirmatory Typing
2.1%
Work-Up
Work-Up
15.8%
1.6%
Transplant
Disadvantages
One unit rescues one patient/no DLI
Readily available
Increased availability for minorities Decreased transmission of viruses (e.g. CMV)
Haplo-identical HSCT
Advantages
Nearly all patients have a donor Share major (e.g. HLA-C) and minor hitocompatibility antigens Immediate donor availability
Disadvantages
HLA Barriers: -Graft rejection -GVHD -Immune dysregulation
4-6 HLA-matched UCB(s) Identified with Cell Dose >1.5 x 107 NC/kg? No Yes
Yes
BMT
UCBT
2,000
1,500 1,000 500 0
NonHodgkin Lymphoma AML Hodgkin Disease Breast Cancer Other Cancer CML MDS/ CLL Other Leukemia ALL NonOvarian Malignant Cancer Disease
Multiple Myeloma
30
Autologous
20
10
Allogeneic
0 1970
1975
1980
1985 Year
1990
1995
2000
B B
B B HSCT
B
B B
A Host B Donor
DLI
A A A AL AL A
B B AL A B
A B
B B
B B B
Recipient
Donor
Mixed Chimera
Complete Chimera
GVHD
GVL Immune reconstitution
Th2 cells
Tc2 cells Id vaccines Cytokines (IL-7)