LATINITAS OR EUROPA – FROM PRESENT TO PAST FROM PAST TO PRESENT.
Transplant: Past Present and Future
-
Upload
silas-lester -
Category
Documents
-
view
23 -
download
3
description
Transcript of Transplant: Past Present and Future
Transplant: Past Present and Future
John McCarty M.D.
Medical Director
Bone Marrow Transplantation Program
Massey Cancer Center
VCU Health Systems/MCV Hospitals and Physicians
May 7, 2008
Introduction
• History of stem cell transplantation
• Definition and biology of stem cells by source
• Practical aspects of the transplant process
• Future directions of BMT
Highlights in Stem Cell Transplant
• Studies of atomic bomb victims showed marrow most sensitive to radiation
• Splenic shielding protected mice from radiation• Bone marrow infusion rescued mice from radiation• Murine and canine models developed for transplant• Discovery that immune response controlled by genetic
factors (histocompatibility factors)• Marrow from histocompatible animals rescues from
lethal radiation
Highlights in Stem Cell Transplant
• 1957: marrow safely infused intravenously
• 1958: reports of successful identical twin transplants
• 1969: Cytoxan added to radiation• 1970: bone marrow harvests
perfected to obtain stem cells• 1989: peripheral blood stem cells
harvested• 1990: first successful cord blood
transplant• 1996: first non-ablative transplant
Thomas et al J Clin Invest 1959
What are Stem Cells?• Not characteristics of specific tissues• Divide for the lifetime of the
organism• Can replenish themselves• Stem cells as “seed cells” for the
body• Stem cells may exist in all organs
– Serve in injury repair– “trust fund” to replace cells as they die
off
• Stem cells may circulate from one tissue reserve to another?
Sources of Stem Cells
• Three main types of stem cells– Adult stem cells
• Main reservoir in the bone marrow
– Cord blood stem cells• Circulating stem cells in
umbilical cord blood
– Embryonic stem cells• Derived from fertilized
embryos during early phases of development
Adult Stem Cells
• Replenish cells lost through age or injury
• Largest reservoir in marrow– Stem cells circulate in blood
– “Relocate” to fill empty stem cell slots in other tissues
• Harvested from bone marrow or peripheral blood in stem cell transplants since late 1970’s
• Stem cells isolated from:– Skin, brain, prostate, muscle
Umbilical Cord Blood Stem Cells
• Obtained from blood retained in the umbilical cord and placenta after delivery
• Has been used in stem cell transplants since the late 1980’s– Most often used in children
and small adults– Potential role for double
cord transplants in adults
QuickTime™ and aGIF decompressor
are needed to see this picture.
Indications for Stem Cell Transplants
• Cancer:– Leukemia– Myelodysplasia– Lymphoma– Breast cancer– Testicular cancer– Ovarian cancer– Brain tumors– Pediatric tumors– Multiple myelomas– Sarcomas– Kidney cancers
• Non Cancers:– Autoimmune diseases
• Rheumatoid arthritis– Juvenile and adult
• Multiple Sclerosis
• Scleroderma
• Systemic Lupus
– Immune deficiency
– Sickle cell anemia
– Thalassemia
Annual Numbers Of Blood And Marrow Transplants Worldwide 1970-2002
NU
MB
ER
OF
TR
AN
SP
LA
NT
S
YEAR
1970 1975 1980 1985 1990 1995
Autologous
Allogeneic
20000
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
45,000
Stem Cell Sources By Recipient Age 1997-2004
Bone Marrow (BM)
Peripheral Blood (PB)
Cord Blood (CB)
Age 20 yrs Age 20 yrs
0
20
40
60
80
100
1997-2000 2001-2004 1997-2000 2001-2004
Tran
sp
lan
ts,
%
Bone Marrow (BM)
Peripheral Blood (PB)
Cord Blood (CB)
Practical BMT
• Two main types based on source of stem cells– Autologous: no immunologic conflict
• Stem cell infusion as “rescue” from high dose chemo
– “marrow lethal dose”
– Allogeneic: Minor HLA disparity•Related•Unrelated•Cord blood
– High dose therapy with immunotherapy» “rejection” of the cancer and building better
immunity
Elements of Stem Cell Transplants
• Selection of donor– Based on tissue typing of 6-10 HLA antigens in allogeneic transplantation– Tissue typing unnecessary in autologous transplantation
• Harvest of stem cells from donor– Bone marrow harvest or pheresis of peripheral blood
• Preparative regimen– Chemo-radiation for ablation and immune suppression
• Stem cell infusion• Post-transplant supportive care
– Autologous 100 days– Allogeneic 180 days or longer for tolerance to develop
Patient Evaluation
• Recipient Age
– Autologous: “0” to 70 years
– Allogeneic:• Matched Related 55-60 years
• Mismatched or Unrelated Donor: 50-55 years» Risk of GVHD significantly increased age >45
• Dose-Adjusted Transplantation for older, or ill patients– Reduced intensity myeloablative
– Non-myeloablative
» Indicated based on extensive pre-transplant evaluation for candidacy
– Patients up to age 70 may be eligible for allogeneic transplant
Preparation for BMT
• Immune suppression and myeloablation required– Bone marrow failure states require more immunosuppression – Immune deficiency without empty marrow leads to rejection.
• Chemotherapy induces aplasia to allow engraftment
• Additional merits of marrow ablation – Provides marrow “space” – Eradicates malignant cells– Reset of the recipient immune system
• Preparative regimens before transplant provide aplasia and immune suppression
HLA and Marrow Transplantation
• Histocompatibility Locus Antigens (HLA) are determinants of immunologic “self” and “not-self”– Immunologic “password”– Allows for effective immune response against infections, cancer
• T cell reaction to foreign HLA molecules (donor) is a major problem of transplantation (alloreactivity)– Need good donor and recipient match for HLA sites– Cause of acute rejection in organ transplant, and of GVHD in
BMT.
HLA Typing in BMT
• Family members typed with patient for HLA A, B and DR– Likelihood of 6/6 or 5/6
match depends on frequency of recipient HLA haplotype
• Likelihood of unrelated donor match related to haplotype frequency in general population– Some HLA combinations
more frequently found among ethnic groups
• Ethnic sequestration phenomenon
Ethnicity and Unrelated Donors
Growth of the Registry has Increased theLikelihood of Matching for All Patients
0%
20%
40%
60%
80%
100%
1988 1990 1992 1994 1996 1998 2000Year
% o
f P
atie
nts
Fin
din
g a
Mat
ch Caucasian 43,780
American Indian/AN, 243
Mult/Oth/Unk/Dec, 7,187
Hispanic, 3,784
Asian/Pacific Islander, 2,328
African American, 4,228
Increasing Donor Pool Essential
• Time from search to unrelated donor: 4 months– Often relapse prevents coming to transplant
• Greater efforts are needed to increase participation and minority representation in the volunteer donor pool (NMDP)– Education regarding safety and need
• Increasing cord blood donation may help some– Everyone has umbilical cord blood they won’t use– No risk to donate– Better reflects the local population demographics
Harvesting Stem Cells
• Adult stem cells obtained by large volume marrow biopsy/aspiration (1-2L)
• Cord blood stem cells obtained at delivery by sterile emptying umbilical cord and placenta into blood donation bag
• Increasingly obtained by processing of peripheral blood of patients and healthy donors– Isolated in “real time” from blood after stimulation with blood
cell growth factors
• Stem cells can be frozen for up to 5-10 years
Practical BMT
• Stem cells infused IV– “Home” to micro-
environment niches in marrow and spleen• Recognition of
arrays of adhesive and growth factors in marrow stroma
• Donor T lymphocytes are essential to engraftment
Hematopoietic Reconstitution• Bone marrow cellularity decreased months post transplant• Immunologic reconstruction over 100 days post transplant
– Graft-vs.-host disease (GVHD) delays immune reconstitution• Immune deficits expected:
– T cell and B cell dysfunction.– Low Ig levels for three months, normal IgG and IgM by one year, IgA by two
year• Predisposes to fungal, viral and bacterial infection
Transplantation Immunology
• In solid organ transplantation, the main relevant immunologic process is graft rejection
• In marrow transplantation, a novel immunologic condition arises due to the immunologic competence of the graft itself.– Rejection is bi-directional
• Graft rejection • Graft-vs.-host disease (GVHD)
– Tolerance develops, immunosuppression not lifelong
Stem Cell Grafts are Complex
GVL,grafting
GVHD
T Lymphocyte functions Stem cell graft components
Stem Cells,progenitors
FacilitatingCells
DendriticCells
NK Cells T and BLymphocytes
Pathophysiology of GVHD
• Essential factors necessary for GVHD to occur:
– Immunologically competent donor graft
– Histo-incompatibility between donor and host
– Immunologically incompetent host
Graft-versus Malignancy Effect
• Lower incidence of leukemic relapse in patients who get acute or chronic GVHD
• Higher relapse rates in syngeneic vs. allogeneic BMT
• High relapse rates in T cell depleted BMT
• Cytogenetic remission induced after post BMT relapse of CML by infusion of donor leukocytes
Nonmyeloablative Stem Cell Transplants as
Immunotherapy• “Mini transplants”: less cytoablative therapy
– host/donor marrow chimerism prominent– early studies effective in CML in patients
up to 75 yrs– low level GVHD
•if chimerism present, malignancy detectable (PCR):
– reduction in immunosuppression– donor lymphocyte infusion– high remission re-induction rate– lower mortality/morbidity
NST: Overview
.
NST: Graft versus Renal Cell Cancer
60 days post transplant 285 days post transplant
Childs et al NEJM 2000
Tandem Transplantation
• Refers to the deliberate performance of two stem cell transplants within 3-4 months of each other– By intention, rather than by failure to respond
• May consist of autologous-autologous or autologous-allogeneic– The latter allows separation of the high dose component from
the immunotherapy component
• Most often utilized in myeloma, testicular cancer, medulloblastoma, neuroblastoma– Response and risk adaptive approach used in myeloma
Cost of BMT
• Variable due to several factors:– Indication: AML<CML<NHL<AA– Complications: hospital days, blood products most $$– Stem cell source: PBSC<Marrow (faster engraftment)– Preparative regimen: TBI expensive– Unrelated>>Allogeneic>Autologous
• Average ABMT 84k-175k
• Average AuBMT 70k-100k
Cost Effectiveness of BMT
• Welch (NEJM 1989): 41 patients with ALL• 17 w/ matched related donor• 19 w/ no donor; standard consolidation/maintenance
– Costs for survivors (both arms) less than non-survivors
– Incremental cost effectiveness (difference in cost/yrs survival):
– BMT: survivor $166k, nonsurvivor $232k– Chemo: survivor $79k nonsurvivor $157k– More patients surviving after BMT
• ICE of BMT $10k per year of life gained– Rx of moderate HTN $13.5k per year of life gained
Long Term Complications• Infection risk prolonged with GVHD• Infertility (Women>>men, TBI>>HD Cytoxan)• Hypothyroid 15-25%; (TBI)• Cataracts (TBI, steroids)• AVN bone: (steroids)• Autoimmune dysfunction: (GVHD)• Dental: dry mouth, caries (GVHD, TBI)• Malignancy 5-6x increased risk PTLPD
– Non hematologic cancer risks from TBI, Cytoxan
New Directions I Autoimmune diseases heterogenous with variable course
All have a basis in the stem cell
Main intervention is immunosuppression Safety and side effect profile improving for stem cell transplant Transplant considered in patients with severe AID
Life-threatening disease Disease of major morbidity (diffuse Scleroderma) unresponsive to standard therapy (Systemic Lupus) Early in progressive relapse (Multiple Sclerosis)
• Preparative regimens to include BU/CY/ATG avoiding TBI reduces risk of secondary malignancy
New Directions II
• Stem cell transplantation as platform for directed therapies– Dendritic cell/NK cell immune therapy– Vehicle for cancer vaccine delivery– Use of specifically generated cytotoxic T cell
lymphocyte responses• Against malignancy• Against infection
– Enhance autologous Graft versus malignancy effect
Developing Applications I
• Induction of solid organ graft tolerance– In living donor solid organ transplants
• Orthotopic liver• Kidney• Pancreatic islet cell
• Tolerance to solid organ by subsequent NST transplantation– Patient as mixed chimera– Transplanted marrow and lymphocytes tolerate patient and
recognize transplanted organ as “self”
Developing Applications II
• Heart disease– Heart muscle damaged by coronary heart disease or
viral injury– Injection of stem cells into area of dead heart muscle
regenerates viable muscle– Injection of stem cells promotes formation of new
blood vessels in injured heart muscle– Can intracoronary or intravenous purified stem cell
populations be given during cardiac catheterization?
Stem Cells Repair Broken Hearts
Orlic et al PNAS 2001
Conclusions
• Stem cells can be derived from adult, cord blood and eventually embryonic stem cells
• Stem cell transplantation can both support highly intensive chemotherapy and promote highly effective immunotherapy
• Recent advances in stem cell transplantation allow therapy more tailored to disease and patient
• Improved supportive care measures expand transplant to more patients
• Expanded applications capitalizing on stem cell plasticity are feasible