Basics of Stem Cell

Transplant
Prof. Dr. Ileana Constantinescu
Background
First successful transplantslate
1960s
30,000-40,000 transplants performed
yearly worldwide
>20,000 patients have survived >5
years

Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3
rd
edition
2002:399-409
Graft Sources
Allogeneic: from another person
Syngeneic: from an identical twin
Autologous: from the patient

Choice of graft is based on disease
type, patient condition, donor
compatibility and health

Graft Sources
Autologous Transplant
No evidence of disease in the blood or
bone marrow
Transplant related mortality (TRM) lowest
with autos (<5%)
Relapse rates are higher depending on
the disease
Absence of graft versus tumor effects
Lazarus HM. Autologous and allogeneic transplantation procedures for hematologic
malignancies. Manual of Clinical Hematology, 3
rd
edition 2002:399-409
Graft Sources
Allogeneic Transplants
High TRM (30-50%)
Lower relapse rates due to graft versus tumor
effects
Graft versus host effects
Matched Related Donor (siblings)
25% chance a sibling will be a match
The more siblings a patient has the better
chance for a match

Lazarus HM. Autologous and allogeneic transplantation procedures for hematologic
malignancies. Manual of Clinical Hematology, 3
rd
edition 2002:399-409
HLA Typing
HLA typing became feasible in 1960s
Linked on chromosome 6
Inherited as haplotypes
1 in 4 chance a sibling will be identical
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-
1826.
HLA alleles
The considerable polymorphism of HLA is well-
known.

HLA polymorphism is reflected by allelic
substitution of many amino acid residues in the
polypeptide chains, especially the external
domains which contain the peptide binding site.

This affects the spectrum of antigenic peptides
presented by the different allelic types of HLA
molecules and the repertoire of responding T-
cells.


The HLA genetics is complex
HLA polymorphism

Expression of HLA polymorphism Typing

The transplanted graft represents a continuous
source of HLA alleles that can induce a rejection
response at any time post-transplant.

HLA matching can have a dualistic effect on
transplant outcome: it reduces rejection but
conversely, it may promote other HLA-restricted
mechanisms of allograft injury.

Fundeni Centre for Immunogenetics and Virology

HLA Matching
6/6, 8/8, or 10/10
HLA loci on chromosome 6
HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ,
HLA-DP
ABO incompatibility is not an exclusion

Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3
rd
edition
2002:399-409
Interpretation of results
Recipient D.F. Donor D.C.
HLA HLA
A 02-24 A 02-24
B 18-18 B 18-18
C 07-07 C 07-07
DRB1 11-13 DRB1 11-13
DQB1 03-05 DQB1 03-05
KIR B4 genotype KIR B4 genotype
KIR 2DL1, 2DL2, 2DL4, 2DL5B, 2DS2,
2DS3, 2DS4
004
, 3DL2, 3DL3, 3DS1,
2DP1, 3DP1
KIR 2DL1, 2DL2, 2DL4, 2DL5B, 2DS2,
2DS3, 2DS4
004
, 3DL2, 3DL3, 3DS1,
2DP1, 3DP1

Fundeni Centre for Immunogenetics and Virology

Recipient A.C. Donor C.R.
HLA HLA
A 03-24 A 03-24
B 18-44 B 18-44
C 05-12 C 05-12
DRB1 16-16 DRB1 16-16
DQB1 05-05 DQB1 05-05
DPB1 02-05 DPB1 02-05
KIR B4 genotype KIR B4 genotype
KIR 2DL1, 2DL2, 2DL4, 2DL5B
003-006
,
2DS3, 2DS4, 2DL1, 3DL2, 3DL3, 2DP1,
3DP1
003

KIR 2DL1, 2DL2, 2DL4, 2DL5B
003-006
,
2DS3, 2DS4, 2DL1, 3DL2, 3DL3, 2DP1,
3DP1
003

Interpretation of results
Fundeni Centre for Immunogenetics and Virology

Interpretation of results
Recipient F.C. Donor F.E.
HLA HLA
A 02-03 A 02-03
B 07-40 B 07-40
C 01-03 C 01-03
DRB1 04-10 DRB1 04-10
DQB1 03-07 DQB1 03-07
KIR A genotype KIR A genotype
KIR 2DL1, 2DL3, 2DL4, 2DS1, 3DL1,
3DL2, 3D33, 2DP1, 3DP1
003

KIR 2DL1, 2DL3, 2DL4, 2DS4, 3DL1,
3DL2, 3DL3, 2DP1, 3DP1
003

Fundeni Centre for Immunogenetics and Virology

Eligibility
Age < 65
Autologous, mini-allo
Age < 55
Myeloablative allogeneic
Exclusions
CHF, uncontrolled diabetes mellitus,
active infections, renal insufficiency
Indications Autologous
Transplant
Multiple myeloma
NHL
Hodgkins disease
AML
Neuroblastoma
Ovarian cancer
Germ-cell tumors
Autoimmune
disorders
Amyloidosis

Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-
1826.
Indications for Allogeneic
Transplant
AML
ALL
CML
MDS
MPD
NHL
Hodgkins Disease
CLL
Multiple myeloma
Juvenile CML
Aplastic anemia
PNH
Fanconis anemia
Blackfan-Diamond
Thalessemia major
Sickle cell anemia
SCID
Wiskott-Aldrich
Inborn errors of
metabolism
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-1826.
Preparative Regimens
Myeloablative
High doses of chemotherapy +/- radiation
3 goals
Eliminate malignancy
Immunosuppression to allow engraftment
Decrease graft versus host effects

Lazarus HM. Autologous and allogeneic transplantation procedures for hematologic malignancies.
Manual of Clinical Hematology, 3
rd
edition 2002:399-409
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-1826.
Myeloablative Regimens
Myeloablative Regimens
Most common regimens
Cyclophosphamide/TBI
Busulfan/Cyclophosphamide
Stem cells are essential to restore
marrow function

Lazarus HM. Autologous and allogeneic transplantation procedures for hematologic malignancies.
Manual of Clinical Hematology, 3
rd
edition 2002:399-409
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-1826.
Myeloablative Regimens
Therapy is based on disease
Other drugs
Etoposide, BCNU, cytarabine, melphalan
Graft versus leukemia effects in
allogeneic donors

Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-
1826.
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3
rd
edition
2002:399-409
Umbilical Cord Blood
1
st
UCB transplant 16 years ago
Child with Fanconis anemia
Cell dose is given per recipient weight
Lower patient weights the high the cell dose
2 x 10
7
nucleated cells/kg
1.7 x 10
7
CD 34+ cells/kg
4/6 match UCB with sufficient cells has a
similar outcome to a matched or one
antigen mismatched MUD
Chao NJ, Emerson SG, Weinberg KI. Stem cell transplantation (Cord
Blood Transplants). Am Soc Hematol Ed Book. 2004:354-371.
Umbilical Cord Blood
Umbilical Cord Blood
Cryopreserved
Small number of stem cells
Higher incidence of engraftment failure
Using more than one unit in adults
Lower risk of GVHD
Degree of matching not as stringent
Chao NJ, Emerson SG, Weinberg KI. Stem cell transplantation (Cord Blood Transplants). Am
Soc Hematol Ed Book. 2004:354-371.
Umbilical Cord Blood
Lower GVHD
TRM not different than MUD
Can be used with myeloablative or
nonmyeloablative conditioning (on a
clinical trial)
Chao NJ, Emerson SG, Weinberg KI. Stem cell transplantation (Cord
Blood Transplants). Am Soc Hematol Ed Book. 2004:354-371.
Complications
Early
Mucositis
Sinusoidal obstructive syndrome (VOD)
Fluid retention, jaundice, hepatomegaly
Transplant related infections
Damage to mouth, gut and skin
Prolonged neutropenia
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-
1826.
Complications
Early
Pancytopenia
PRBC and platelet transfusions
Broad spectrum antimicrobials
Antifungals if prolonged fevers 3-5 days
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3
rd
edition
2002:399-409
Complications
Early
Graft Versus Host Disease
Acute GVHD to day 100
Skin, GI tract, liver
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3
rd
edition
2002:399-409
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-
1826.
GVHD
In GVH diseases donor-derived immuno-competent lymphocytes
react with HLA incompatible recipient cells and induce inflammatory
responses in host tissues such as the skin and gastrointestinal tract.


GVH disease seems more likely in cases whereby the donor is well
matched for the patient.


Direct and indirect HLA allorecognition mediate GVH reactions if
immunocompetent donor cells recognize recipient incompatibilities.


During infection, microbial antigens are processed by APC and
presented via HLA molecules to T-cells that elicit cytotoxic and DTH-
like inflammatory reactions in the allograft.



Fundeni Centre for Immunogenetics and Virology

Complications
Early
Graft Rejection
Host versus graft
Drug injury to marrow
Viral infections: CMV, HHV-6 & 8
Interstitial Pneumonitis
Diffuse alveolar hemorrhage
Too few donor stem cells
ARDS often caused by CMV
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3
rd
edition
2002:399-409
Complications
Delayed
Chronic GVHD
Scleroderma or Sjogrens syndrome
Bronchiolitis
Keratoconjunctivitis
Malabsorption
Cholestasis
Esophageal stricture

Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-
1826.
Late Complications
Secondary Tumors
Acute leukemias, solid tumors, MDS
Months to years after transplant
Increased incidence with TBI
Late Infections
Bacterial, viral fungal
Months after transplant
Associated with GVHD
Need repeat vaccinations
Pneumovax, Hep B, Hemophilus influenza b, poliovirus,
diphtheria/tetanus, flu
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3
rd
edition
2002:399-409