Download John McCarty MD Medical Director Bone Marrow Transplantation

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
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Indications for Stem Cell Transplants
• Cancer:
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–
–
–
–
–
–
–
–
–
–
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
NUMBER OF TRANSPLANTS
Annual Numbers Of Blood And Marrow Transplants
Worldwide 1970-2002
45,000
40,000
35,000
Autologous
30,000
25,000
20,000
15,000
10,000
Allogeneic
5,000
0
1970
1975
1980
1985
YEAR
1990
1995
2000
Stem Cell Sources By Recipient Age 1997-2004
Transplants, %
100
Bone Marrow
Marrow (BM)
(BM)
Bone
Peripheral Blood
Blood (PB)
(PB)
Peripheral
Cord Blood
Blood (CB)
(CB)
Cord
80
60
40
20
0
1997-2000
2001-2004
Age 20 yrs
1997-2000
Age >20 yrs
2001-2004
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
% of Patients Finding a Match
Growth of the Registry has Increased the
Likelihood of Matching for All Patients
100%
Caucasian 43,780
80%
American Indian/AN, 243
60%
Mult/Oth/Unk/Dec, 7,187
40%
Hispanic, 3,784
20%
Asian/Pacific Islander, 2,328
African American, 4,228
0%
1988 1990 1992 1994 1996 1998 2000
Year
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 microenvironment 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
Stem cell graft components
Facilitating
Cells
Dendritic
Cells
Stem Cells,
progenitors
NK Cells
T Lymphocyte functions
T and B
Lymphocytes
GVHD
GVL,
grafting
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
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 autologousallogeneic
– 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:
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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
• Average AuBMT
84k-175k
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
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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
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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
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