Transcript Introduction to Hematopoietic Stem Cell

HSC: Key Definition
• Haematopoietic Stem Cell
 Cell produced in bone marrow that gives rise to all
other blood cells (white cells, red cells, and platelets)
• Replenishes itself
• Relatively resistant to injury
• But, that can be eliminated with high doses of chemotherapy or
radiation therapy
Haematopoietic Stem Cell
HSCT: Key Vocabulary
• Stem Cell Transplant
to re-infuse HSC in patients who have received high doses
of chemotherapy and/or radiation therapy
• Allogeneic transplant
uses stem cells from another person (who is a perfect
match)
• Autologous transplant
uses stem cells taken from the patient
Types of Transplants
• Autologous
• Allogeneic
• Syngeneic
Concepts of HSC Transplant
• Allows delivery of high dose chemotherapy and/or
total body irradiation
 Destruction of tumor
 Creation of marrow space
 Prevention of *graft rejection
*stem cells from allo donor
Diseases Commonly Treated with HSCT.
Indications for Blood & Marrow
Transplantation in North America, 2002
Overall Numbers of Stem Cell
Transplant
HSCT
How is it done?
Patients are carefully screened
 Disease responsive to HSCT(i.e.., AML, NHL)
 Comorbidities and Performance Status (CHF, COPD, CRI)
 Infectious diseases Profile (i.e.. HIV, Hepatitis, etc)
Stem cells are collected.
From the patient (for autologous HSCT)
or the donor (allogeneic)
Stem Cell Graft Collection
• Marrow
• Peripheral Blood
• Patient’s own or from somebody else
Source of Haematopoietic Stem Cells
• Bone Marrow
 Requires general anesthesia in operating room
 Traditional method
• Peripheral Blood (drawn from veins)
 Obtained by apheresis
 Accomplished as outpatient procedure
 Currently most commonly utilized method
Number of Stem Cells Circulating in Peripheral Blood
Haematopoietic Stem Cell Graft
HSC: Procurement Concepts
• Amount of stem cells collected based on recipients
body weight
• Minimal number
 2 x 108/kg nucleated cells
 2 x 106/kg CD 34 + cells
• CD-cluster differentiation
• Flow Cytometry
HSC from Peripheral Blood Collection
• Translated on:
Mortality rate for autologous transplantation is expected to
be below 5%.
Development of Outpatient Transplantation Programs.
Autologous Stem Cell Sources by
Recipient Age, 1996-2002
Trends In Autologous Transplants by
Recipient Age, * 1990-2002
HSCT Process: Kill the Cancer, Injure
the Patient
• Patients are treated with high-dose chemotherapy
and/or radiation.
• Stem Cells are infused (IV) back to the patient.
• Patient supported with antibiotics, blood
transfusions, and treatment for other side-effects
Bone Marrow Ablation:
High Dose Chemotherapy and TBI Administration
Common Complications after HSCT
Mucositis
Stem Cell Engraftment
• Engraftment of new stem cells generally takes 10-21 days
• Patient heals the mucositis
• Resolves the infectious process
• Hope the Cancer was Eliminated
Transplantation: Long-Term Outcomes
Types of Transplants: Why Allogeneic
Autologous versus allogeneic
 Marrow and Blood “contaminated” with malignant cells.
 Stem cells affected by the disease.
 No Stem cells available for collection
Bone Marrow Ablation:
High Dose Chemotherapy and TBI Administration
Allogeneic HSCT
When stem cells come from a healthy donor, stem cells are
“clean” of Malignant Disease,
(Donor has to be carefully screened about Infectious diseases too)
Grafts, from Donors other than the Patient (sibling or
unrelated), bring another weapon to kill the Disease:
Graft versus Tumor (GVT) effect
Graft versus Tumor, is the condition where donor T-Cells
recognize recipients tumor (i.e., Leukemia) and builds an
immune reaction to systematically destroy the tumor
Allogeneic Transplantation with Full or ReducedIntensity Preparative Regimens
Allogeneic HSCT
• Allogeneic Stem cells will eventually completely eradicate
the patient bone marrow (blood making) and immune
system
• A new bone marrow and immune system is built all with
cells from the allo donor
• This process allows the elimination of the tumor, Graft
versus Tumor, at a cost of an enormous immunosupression
and Graft vs. Host Disease
Graft-versus-Leukemia Effect from a Minor
Histocompatibility Antigen.
Copelan, E. A. N Engl J Med 2006;354:1813-1826
Postulated Mechanism of Acute GVHD.
Graft versus Tumor
Graft Versus Patient
Limitations of Allogeneic HSCT
• Scarcity of suitable donors
25% sibling match, not everybody has a donor
• Graft versus Host Disease
• Infections
Complications after HSCT
Graft Versus Host Disease
• Condition where donor T-Cells recognize recipient as
foreign and attacks the patient skin, bowel, liver, and other
tissues
• This graft-versus-host reaction leads to GVHD signs and
symptoms
HLA Typing
Human Leukocyte Antigen
• HLA are proteins found on short arm of chromosome 6
• 3-antigens important in HSCT,
 HLA-A
 HLA-B
 HLA-DR
one set of 3 from each parent
• Brings to a total of six antigens to match
• A full match is “6/6” or “perfect” match
HLA Typing
Human Leukocyte Antigen
Mother
Father
25 % chance that each sibling will match
HLA or Tissue Typing
• Rate of GVHD
Donor
6/6
5/6
4/6
3/6
Incidence
40%
50%
80%
90%
GVHD Prophylaxis
Graft vs. Host Disease GVHD
• Acute
• Chronic
Up to Day +100
After Day +100
• Skin
• Liver
• Gut
•
•
•
•
•
Skin
Mucous Membranes
Gut
Liver
Scleroderma
Acute GVHD Grading
Acute GVHD Grading
Acute GVHD: Skin
Lichenoid Lesions of Chronic Graft-versus-Host
Disease.
Graft-versus-Host Disease of the Skin
Antin, J. H. N Engl J Med 2002;347:36-42
Acute and Chronic GVHD Therapy
• Steroids and Cyclosporine / Tacrolimus
• Other modalities of immunosupression
Late Complications of Allogeneic
HSCT
• 50-60% may develop chronic GVHD
• Chronic GVHD
GVHD after day +100, single major determinant of patients
outcome and quality of life after HSCT.
• Immunosupression and Infections
Fungal Infections (Aspergillum), viral reactivation (CMV,
HS)
Outcomes of Haematopoietic Stem-Cell
Transplantation: Allogeneic
Outcomes of Haematopoietic Stem-Cell
Transplantation in Selected Diseases
Copelan, E. A. N Engl J Med 2006;354:1813-1826
Potential/Future Applications
• Autoimmune Disorders
 Rheumatoid Arthritis
 Lupus
 Multiple Sclerosis
• Other Disorders
 Congestive Heart Failure
CHS-HSCT Program
LS CMC 5th
Floor