Bone marrow transplantation involves harvesting stem cells from either the patient (autologous) or a donor (allogeneic) and administering high-dose chemotherapy to eliminate malignant or damaged bone marrow cells. Allogeneic transplants can provide a graft-versus-tumor effect from donor immune cells attacking cancer cells, but also risk graft-versus-host disease as donor cells may attack patient tissues. The choice of donor, degree of tissue matching, and immuno-modulation of the graft influence efficacy and complications like relapse and GVHD. Further research aims to maximize the graft-versus-tumor effect while minimizing graft rejection and side effects.
2. Bone Marrow TransplantationBone Marrow Transplantation
AutologousAutologous - stem cells from the patient- stem cells from the patient
harvested during completeharvested during complete
remissionremission
AllogeneicAllogeneic - harvested from a matching- harvested from a matching
healthy donorhealthy donor
3. Autologous BMTAutologous BMT
Efficacy based on higher dose of chemotherapyEfficacy based on higher dose of chemotherapy
Irreversible
multi-organ
toxicity
Myeloablative
dose levels
4. Autologous BMTAutologous BMT
Cells are harvested from peripheral blood whenCells are harvested from peripheral blood when
the patient is considered to be in completethe patient is considered to be in complete
remission or when the tumor burden is low (inremission or when the tumor burden is low (in
this instance the intention isthis instance the intention is notnot curativecurative((
High dose chemotherapy with or withoutHigh dose chemotherapy with or without
radiation is administered in order to eradicateradiation is administered in order to eradicate
or to maximally reduce the population ofor to maximally reduce the population of
malignant cellsmalignant cells
5. Autologous BMTAutologous BMT
Stem cells are infused intravenously to overcomeStem cells are infused intravenously to overcome
the toxicity to the bone marrowthe toxicity to the bone marrow
High Dose Chemotherapy with AutologousHigh Dose Chemotherapy with Autologous
Stem Cell SupportStem Cell Support
7. Autologous BMTAutologous BMT
LimitationsLimitations::
--Ineffective for chemo-resistant diseaseIneffective for chemo-resistant disease
--Contamination of graft by malignant cellsContamination of graft by malignant cells
--Low efficacy - relapse of primary diseaseLow efficacy - relapse of primary disease
AdvantagesAdvantages::
--Ready availabilityReady availability
--No GVHNo GVH
--No blood-transmitted infectionsNo blood-transmitted infections
8. Autologous BMTAutologous BMT
ComplicationsComplications::
--Severe infections due to prolonged neutropeniaSevere infections due to prolonged neutropenia
--Prolonged bone marrow dysfunctionProlonged bone marrow dysfunction
--Non-marrow toxicityNon-marrow toxicity
--Secondary malignanciesSecondary malignancies
12. Allogeneic BMTAllogeneic BMT
Cells are harvested from the pelvic bones orCells are harvested from the pelvic bones or
from the peripheral blood of afrom the peripheral blood of a donordonor::
--Fully matched related donor (usuallyFully matched related donor (usually
brother/sisterbrother/sister((
--Matched non-related donor (MUDMatched non-related donor (MUD((
--Related haplo-identical donor (parents/kidsRelated haplo-identical donor (parents/kids((
--Partially matched related/non-related donorPartially matched related/non-related donor
13. HLA MatchingHLA Matching
HLA genes are part of Major HistocompatibilityHLA genes are part of Major Histocompatibility
Complex that encodeComplex that encode proteins associated withproteins associated with
antigen-presentationantigen-presentation
Two main groups are recognized: class I (presentTwo main groups are recognized: class I (present
on all cells) and class II (present on some cellson all cells) and class II (present on some cells
of the immune systemof the immune system((
Class I genes includeClass I genes include A, B and CA, B and C lociloci
Class II genes includeClass II genes include DR, DQ and DPDR, DQ and DP lociloci
14. HLA MatchingHLA Matching
Bone marrow donor is considered to beBone marrow donor is considered to be matchedmatched
when his genes are similar to those of thewhen his genes are similar to those of the
recipient at therecipient at the A, B, C and DRA, B, C and DR loci (twoloci (two
alleles for each locusalleles for each locus –– 8 altogether8 altogether((
Related donorsRelated donors also have a high chance to matchalso have a high chance to match
at other loci (Minor Histocompatibility) whichat other loci (Minor Histocompatibility) which
are not well defined and not checkedare not well defined and not checked
Mismatch at 1 or even 2 lociMismatch at 1 or even 2 loci does notdoes not precludepreclude
transplantationtransplantation
15. Mismatch at Which Loci ImpactsMismatch at Which Loci Impacts
SurvivalSurvival??
AA BB CC DRDR DQDQ
JMDPJMDP YesYes NoNo NoNo
FHCRCFHCRC YesYes YesYes
NMDPNMDP YesYes YesYes YesYes YesYes NoNo
16. Allogeneic BMTAllogeneic BMT
--Fully matched related donor is usuallyFully matched related donor is usually
preferred for most types of BMTpreferred for most types of BMT
--However, each donor type has its advantagesHowever, each donor type has its advantages
and disadvantagesand disadvantages
--Stem cells obtained fromStem cells obtained from cord bloodcord blood are moreare more
and more frequently used for transplantationand more frequently used for transplantation
19. Allogeneic BMTAllogeneic BMT
AdvantagesAdvantages::
--High efficacyHigh efficacy (AML: 30-60% ALL: ~40%(AML: 30-60% ALL: ~40%((
--No contamination of bone marrow graftNo contamination of bone marrow graft
LimitationsLimitations::
--Severe side effects (GVHSevere side effects (GVH((
--Limited availability of grafts (for unrelatedLimited availability of grafts (for unrelated
donors depends on the ethnic origindonors depends on the ethnic origin((
--Transmission of blood-borne infectionsTransmission of blood-borne infections
20. GVH (Graft versus Host DiseaseGVH (Graft versus Host Disease((
--Effect of donor lymphocytes against the tissuesEffect of donor lymphocytes against the tissues
of the host (recognized as non-selfof the host (recognized as non-self((
--Related (butRelated (but notnot identical) to GVLidentical) to GVL –– somesome
patients develop the one, but not the otherpatients develop the one, but not the other
--Can be acute or chronic; varies in severity fromCan be acute or chronic; varies in severity from
a mild to a rapidly fatal diseasea mild to a rapidly fatal disease
28. GVHGVH
For most patients effective therapy for GVH isFor most patients effective therapy for GVH is
readily availablereadily available
However, elimination of Graft vs HostHowever, elimination of Graft vs Host
response usually eliminates the Graft vsresponse usually eliminates the Graft vs
Leukemia/Lymphoma effect as wellLeukemia/Lymphoma effect as well
29. Similarly, elimination of T cells from the graftSimilarly, elimination of T cells from the graft
prevents severe GVH, but severely reduces theprevents severe GVH, but severely reduces the
GVL effectGVL effect
Months after BMT
Probabilityofrelapse
45
30. Non-myeloablative SCT
The goal & the rationale
Attempt to eradicate all tumor cells
prior to BMT and use hematopoietic
cells for rescue of the patient
Tumor elimination mostly
before transplantation !!!
Maximize conditioning
The goal & the rationale
1. Donor stem cells for tolerance
2. Donor T & NK cells for
GVL/GVT
Tumor elimination mostly
late post transplantation !!!
Minimize conditioning
62
32. Allogeneic BMTAllogeneic BMT
SummarySummary::
--Highly effective in many otherwise untreatableHighly effective in many otherwise untreatable
diseasesdiseases
--Efficacy may depend on the choice of donorEfficacy may depend on the choice of donor
and on immuno-modulation of the graftand on immuno-modulation of the graft
--GVHGVH –– severe and potentially lethalsevere and potentially lethal
complicationcomplication
--Efficient application depends on futureEfficient application depends on future
researchresearch