Daniel R Couriel, MD

1
Overview of Hematopoietic Stem Cell
Transplantation (HSCT)

• Daniel R Couriel, MD
• Sarah Cannon Blood and Marrow Transplant Program

2
Hematopoiesis
T-lymphocytes
Stem Cells
B-lymphocytes
Granulocytes
Monocytes
Eosinophils
Basophils
Erythrocytes
Megakaryocytes
Platelets
3
Hematopoietic Stem Cell Transplantation
D
D
D
D
D
D
D
D
HSCT
Allogeneic
Autologous
R
R
Preparative Regimen
R
R
R
R
R
R
R
RL
RL
R
Allogeneic hematopoietic is an effective, but
toxic treatment for hematologic malignancies,
associated with a high risk of morbidity and
mortality (10-gt50), restricting its use to young
patients without comorbidities
4
(No Transcript)
5
(No Transcript)
6
(No Transcript)
7
(No Transcript)
8
Types of HCT Histocompatibility
Autologous HCT
Allogeneic HCT

• HLA-identical sibling
• HLA-matched unrelated donor (MUD)
• HLA-mismatched donor

Patients own cells

• Choice of Transplant Type
• Disease susceptibility to chemotherapy
• Ability to eradicate malignant clones

9
Autologous vs. Allogeneic

• Autologous
• High dose therapy with reinfusion of own
  cryopreserved cells
• Safer, TRM lt5
• Possible contamination with malignant cells
• No Graft-vs-malignancy effect
• Higher risk of relapse

• Allogeneic
• Immunosuppressive Rx with infusion of cells from
  another person
• Risk of rejection, GVHD
• Higher risk, TRM 10-40
• Graft-vs-malignancy (GVM) occurs
• Lower risk of relapse
• Can perform in diseases in which blood and BM
  involved

10
Sensitivity/resistance to GVM

• Indolent diseases (CML, CLL, LGL)
• Intrinsic sensitivity /or time for development
  of GVM
• Rapidly proliferating disease may outpace immune
  response
• Effective antigen presentation, costimulation
  (capacity to generate an immune response)
• CML dendritic cells, LGL
• ALL ineffective costimulation
• Chemotherapy resistance
• Chemorresistance may also affect sensitivity to
  immune mediated cytotoxicity

11
Nonablative/Reduced Intensity Regimens
Nonablative Reduced Intensity Ablative
TBI/CyT
TMF
F-TBI 2Gy
BuCy
BuF
Immunosuppression
MF
FCR
TC
TBI 2Gy
FlagIda
Myelosuppression
12
General Eligibility Criteria

• Autotransplant Physiologic age 70, minimal
  comorbidities
• Allotransplant Physiologic age 65, although
  patients with comorbidities or elderly (to
  chronologic age of 75) can be considered for
  reduced intensity HSCT
• Comorbidities To be evaluated in the context of
  risk/benefit ratio
• Chemosensitivity Precondition in the majority of
  diagnoses, particularly in DLCL, ALL, BC of CML.

13
Transplant Patient Flow in a Nutshell

• Pretransplant Evaluation and donor search and
  collection
• Inpatient Admission for chemotherapy,
  preparative regimen, acute GVHD
• Ambulatory treatment Center (allo)/Outpatient
  (auto) From D/C to Day 100 (or beyond if
  complications occur)
• LTFU phase in the outpatient clinic (cGVHD and
  other long term, survivorship issues)

14
ANNUAL NUMBERS OF BLOOD AND MARROW TRANSPLANTS
WORLDWIDE1970-2002
Autologous
NUMBER OF TRANSPLANTS
Allogeneic
1970
1975
1980
1985
1990
1995
2000
YEAR
1
15
INDICATIONS FOR ALLOGENEIC BLOOD AND MARROW
TRANSPLANTS REGISTERED WITH THE IBMTR,
1997-2002- Worldwide -
14,000
12,000
10,00
8,000
TRANSPLANTS
6,000
4,000
2,000
0
AML
OtherNon-MalignantDisease
CML
ALL
MDS/MPSOtherLeukemia
NHL
MultipleMyeloma
CLL
HodgkinDisease
RenalCell
OtherCancer
SAA
17
16
PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL
SIBLING MYELOABLATIVE TRANSPLANTS FOR LEUKEMIA-
Registered with the IBMTR, 1975-2002 -
³1995 (N15,126)
1985-1994 (N14,755)
PROBABILITY,
1975-1984 (N2,334)
P 0.0001
YEARS
Mln04_3.ppt
17
Complications after HSCT (non-immunologic)

• Short and long term toxicities of preparative
  regimen
• Secondary malignancies

18
Immune Reactivity with BMT

• Graft-rejection
• Recipient (host) immune cells react against donor
  cells
• T-cells, NK cells
• Graft-vs-host disease
• Donor cells react against host tissues
• T-cells
• Immune deficiency
• Profound deficiency of T-cells and B cells (CD4
  slower recovery than CD8),
• Most severe in first 100 days
• Slow recovery during first year
• Graft-vs-malignancy effects
• T-cells or NK cells react against residual
  malignancy

19
Human Leukocyte Antigens

• Histocompatibility antigens are cell surface
  determinants that mediate immune reactions and
  graft rejection after transplantation between
  genetically diverse individuals.
• T cells will recognize antigens presented as
  peptide fragments associated to HLA molecules.

20
HLA complex on chromosome 6
21
HLA Matching

• A, B, C, DRB1, DQB1 - 10 out of 10 match
• Molecular typing (allele level) - eg for class II
  (DRB1, DQB1)

22
Engraftment
Graft
Host
Stem cell dose T-cell dose (CD8) Graft-facilitatin
g cells Stromal stem cells?
Immunosuppression Preparative Regimen Post
transplant Rx Disease effects
Sensitization
Histocompatibility
With reduced immunosuppression in current NST
regimens, graft cells (stem, T-, NK- and
accessory cells) important to overcome rejection
23
Acute GVHD

• Due to reactivity of mature T-cells in the
  graft vs. recipient (host) tissues, augmented by
  inflammatory cytokines
• Targets- Skin, liver, GI tract
• Immune system and marrow also a target
• Usually occurs within the first 100 days

24
(No Transcript)
25
(No Transcript)
26
(No Transcript)
27
(No Transcript)
28
Chronic GVHD

• Most frequent late complication of allogeneic BMT
• Occurs in 1/3 to 1/2 of patients
• Most frequent in patients with acute GVHD, but
  1/3 of cases develop de novo
• More frequent with older age
• More frequent with PBSC transplants
• Treatment- steroids /- other agents
• Trade off immunosuppression improves
  manifestations of GVHD, but increases risk of
  infection

29
Lichenoid GVHD
30
Sclerosis
31
Sclerosis/Ulcer
32
Lichenoid changes, Lichen sclerosus, Sclerosis/Mor
phea, Poikiloderma, Dyspigmentation
33
Fasciitis Deep sclerosis
34
Lichenoid GVHD of the lips
35
Lichenoid GVHD with hyperkeratotic changes and
ulcerations
36
Late Complications of BMT

• Secondary Malignancies
• Cirrhosis (multifactorial, transfusions, toxicity
  of prior chemo, alcohol, GVHD)
• Late infections (CMV, fungi if on steroids or
  cGVHD, encapsulated bacteria,)
• EBV lymphoproliferative disease
• Most patients return to normal or near normal
  performance status

37
Conclusions

• HCT is an effective therapy for several types of
  hematologic malignancies
• Autologous transplants are associated with a
  transplant-related mortality (TRM) similar to
  that of chemotherapy, but has the disadvantage of
  no GVM and therefore the potential for a higher
  relapse rate
• Allogeneic transplants have a comparatively
  higher TRM, and GVHD is a major complication. The
  risk and commitment is substantially higher, but
  it is the price we have to pay for GVM and a
  long-term remission in select situations