Transcript Basics of Stem Cell Transplant

Basics of Stem Cell
Transplant
Prof. Ileana Constantinescu
Background
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First successful transplants—late
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, 3rd edition
2002:399-409
Graft Sources
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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
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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, 3rd edition 2002:399-409
Graft Sources
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Allogeneic Transplants
– High TRM (30-50%)
– Lower relapse rates due to graft versus tumor
effects
– Graft versus host effects
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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, 3rd edition 2002:399-409
GRAFT VS. HOST DISEASE
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This disease occurs when an immunologically competent foreign graft
containing T cells reacts against the MHC antigens of an immunologically
compromised host.
In general, concerns regarding the outcome of transplantation
represent a one-way street, namely the potential of the immune system
of a transplant recipient or host to reject a transplant. An interesting
reversal of the direction of the immune response occurs, however,
when immunocompetent cells (spleen cells) are transplanted into
a host whose immune system is not functioning properly (irradiated)
and is, therefore, immunosuppressed.
In this case, a phenomenon known as graft vs. host disease
ensues, where the immunocompetent graft directs an immunological
assault against the host, sometimes with fatal consequences.
Graft vs. host disease is, therefore, of particular concern in cases of
bone marrow transplantation, where immunocompetent T cells in
the graft tissue can direct a graft rejection response against the cell
surface MHC antigens of a frequently immunocompromised recipient or
host.
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HLA Typing
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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;354:18131826.
HLA alleles
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The considerable polymorphism of HLA is wellknown.
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 Tcells.
The HLA genetics is complex
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HLA polymorphism
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Expression of HLA polymorphism –Typing
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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.
HLA Matching
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6/6, 8/8, or 10/10
– HLA loci on chromosome 6
– HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ,
HLA-DP
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ABO incompatibility is not an exclusion
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd 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, 2DS4004, 3DL2, 3DL3, 3DS1,
2DP1, 3DP1
KIR –2DL1, 2DL2, 2DL4, 2DL5B, 2DS2,
2DS3, 2DS4004, 3DL2, 3DL3, 3DS1,
2DP1, 3DP1
Interpretation of results
Recipient A.C.
Donor C.R.
HLA
HLA
A 03-24
B 18-44
C 05-12
DRB1 16-16
DQB1 05-05
DPB1 02-05
A 03-24
B 18-44
C 05-12
DRB1 16-16
DQB1 05-05
DPB1 02-05
KIR – B4 genotype
KIR – B4 genotype
KIR –2DL1, 2DL2, 2DL4, 2DL5B003-006,
2DS3, 2DS4, 2DL1, 3DL2, 3DL3, 2DP1,
3DP1003
KIR –2DL1, 2DL2, 2DL4, 2DL5B003-006,
2DS3, 2DS4, 2DL1, 3DL2, 3DL3, 2DP1,
3DP1003
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, 3DP1003
KIR – 2DL1, 2DL3, 2DL4, 2DS4, 3DL1,
3DL2, 3DL3, 2DP1, 3DP1003
Eligibility
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Age < 65
– Autologous, mini-allo
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Age < 55
– Myeloablative allogeneic
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Exclusions
– CHF, uncontrolled diabetes mellitus,
active infections, renal insufficiency
Indications Autologous
Transplant
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Multiple myeloma
NHL
Hodgkin’s disease
AML
Neuroblastoma
Ovarian cancer
Germ-cell tumors
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Autoimmune
disorders
Amyloidosis
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:18131826.
Indications for Allogeneic
Transplant
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AML
ALL
CML
MDS
MPD
NHL
Hodgkin’s Disease
CLL
Multiple myeloma
Juvenile CML
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Aplastic anemia
PNH
Fanconi’s 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
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Myeloablative
– High doses of chemotherapy +/- radiation
– 3 goals
Eliminate malignancy
 Immunosuppression to allow engraftment
 Decrease graft versus host effects
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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, 3rd edition 2002:399-409
Myeloablative Regimens
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Myeloablative Regimens
– Most common regimens
Cyclophosphamide/TBI
 Busulfan/Cyclophosphamide
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Stem cells are essential to restore
marrow function
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, 3rd edition 2002:399-409
Myeloablative Regimens
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Therapy is based on disease
Other drugs
– Etoposide, BCNU, cytarabine, melphalan
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Graft versus leukemia effects in
allogeneic donors
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd edition
2002:399-409
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:18131826.
Umbilical Cord Blood
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1st UCB transplant 16 years ago
– Child with Fanconi’s anemia
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Cell dose is given per recipient weight
– Lower patient weights the high the cell dose
– 2 x 107 nucleated cells/kg
– 1.7 x 107 CD 34+ cells/kg
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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
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Umbilical Cord Blood
– Cryopreserved
– Small number of stem cells
– Higher incidence of engraftment failure
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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
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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
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Early
– Mucositis
– Sinusoidal obstructive syndrome (VOD)
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Fluid retention, jaundice, hepatomegaly
– Transplant related infections
Damage to mouth, gut and skin
 Prolonged neutropenia
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Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:18131826.
Complications
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Early
– Pancytopenia
PRBC and platelet transfusions
 Broad spectrum antimicrobials
 Antifungals if prolonged fevers 3-5 days
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Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd edition
2002:399-409
Complications
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Early
– Graft Versus Host Disease
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Acute GVHD to day 100
– Skin, GI tract, liver
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:18131826.
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd edition
2002:399-409
GVHD
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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 DTHlike inflammatory reactions in the allograft.
Complications
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Early
– Graft Rejection
Host versus graft
 Drug injury to marrow
 Viral infections: CMV, HHV-6 & 8
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– Interstitial Pneumonitis
Diffuse alveolar hemorrhage
 Too few donor stem cells
 ARDS often caused by CMV
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Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd edition
2002:399-409
Complications
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Delayed
– Chronic GVHD
Scleroderma or Sjogrens syndrome
 Bronchiolitis
 Keratoconjunctivitis
 Malabsorption
 Cholestasis
 Esophageal stricture
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Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:18131826.
Late Complications
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Secondary Tumors
– Acute leukemias, solid tumors, MDS
– Months to years after transplant
– Increased incidence with TBI
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Late Infections
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Bacterial, viral fungal
Months after transplant
Associated with GVHD
Need repeat vaccinations
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Pneumovax, Hep B, Hemophilus influenza b, poliovirus,
diphtheria/tetanus, flu
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd edition
2002:399-409
Human herpesvirus 6 infection in hematopoietic cell
transplant recipients
Human herpesvirus 6 (HHV-6) is a member of the Roseolovirus genus of the beta-herpesvirus
subfamily of human herpesviruses. There are two HHV-6 variants, HHV-6A and HHV-6B. Based on
their distinctive biological properties and genome sequences, the Herpesvirales Study Group of the
International Committee on Taxonomy of Viruses has classified HHV-6A and HHV-6B as two distinct
herpesvirus species.
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The vast majority of documented primary infections and reactivation events are due to HHV-6B. HHV6B infects most children within the first three years of life and, like other herpesviruses, it establishes
latency after primary infection. HHV-6B may reactivate in immunocompromised hosts, especially
following allogeneic hematopoietic cell transplantation (HCT). Encephalitis is the most clearly
established clinical manifestation of HHV-6 reactivation in allogeneic HCT recipients, and may result in
substantial morbidity. Little is known about the epidemiology or clinical implications of HHV-6A.
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The epidemiology, clinical manifestations, diagnosis, and treatment of HHV-6 infections in HCT
recipients will be discussed here. HHV-6 infections in patients who are not HCT recipients are
presented separately.
EPIDEMIOLOGY
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Human herpesvirus 6 (HHV-6) reactivation occurs in 30 to 70 percent of patients undergoing
allogeneic hematopoietic cell transplantation (HCT) , with encephalitis occurring in only a small subset
of these patients. HHV-6 reactivation often manifests as HHV-6 viremia, and typically occurs between
two and four weeks after transplantation. HHV-6B accounts for most reactivations, with HHV-6A
accounting for fewer than 3 percent of cases.
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Risk factors — Both demographic and clinical factors may influence the risk of HHV-6 reactivation.
As an example, recipients of allogeneic HCT are at higher risk of HHV-6 reactivation than recipients of
autologous HCT; among allogeneic HCT recipients, those who receive transplants from unrelated or
HLA-mismatched donors are at particularly increased risk .
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Romanian BMR
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Started in 2003
EFI Accredited in 2006
Holds details of stem cell donors and cord
donations from Moldavia, Transilvania,
Banat, Black Sea Coast, Walachia.
We need to contiue to recruit more donors,
particularly from ethnic communities
HLA DNA 2 digits typed for HLA A, B, C,
DRB1 and DQB1