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Bone MarrowBone Marrow
TransplantationTransplantation
Marcelo dos SantosMarcelo dos Santos
B.Med.Lab.ScB.Med.Lab.Sc..
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
Autologous BMTAutologous BMT
 Efficacy based on higher dose of chemotherapyEfficacy based on higher dose of chemotherapy
Irreversible
multi-organ
toxicity
Myeloablative
dose levels
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
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
Autologous BMTAutologous BMT
IndicationsIndications::
LeukemiaLeukemia)?()?(
Aggressive LymphomaAggressive Lymphoma Curative IntentCurative Intent
HodgkinHodgkin’’s diseases disease
Indolent LymphomaIndolent Lymphoma
Multiple MyelomaMultiple Myeloma
SupportiveSupportive Intent
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
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
Allogeneic BMTAllogeneic BMT
 Efficacy based onEfficacy based on Graft versus TumorGraft versus Tumor effecteffect
47
Allogeneic lymphocytes attackAllogeneic lymphocytes attack
a blasta blast
48
The blast explodes
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
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
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
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
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
MUDMUD UCBTUCBT MismatchedMismatched
familyfamily
PROsPROs • No TCDNo TCD
• GVLGVL
• TimeTime
• Less GVHDLess GVHD
• TimeTime
• Less GVHDLess GVHD
• Post SCTPost SCT
cell therapycell therapy
• FastFast
engraftmentengraftment
CONsCONs • TimeTime
• CostCost
• GVHDGVHD
• infectionsinfections
• Post SCTPost SCT
cell therapycell therapy
• CostCost
• InfectionsInfections
• ReducedReduced
GVLGVL
• SlowSlow
engraftmentengraftment
• Post SCTPost SCT
cell therapycell therapy
• MandatoryMandatory
TCDTCD
• Graft lossGraft loss
• InfectionsInfections
• ReducedReduced
GVLGVL
Allogeneic BMTAllogeneic BMT
Indications for allogeneic BMTIndications for allogeneic BMT::
--Malignant diseases (leukemia, lymphoma,Malignant diseases (leukemia, lymphoma,
renalrenal
cell carcinomacell carcinoma((
--Non-malignant hereditary diseasesNon-malignant hereditary diseases::
--thalassemiathalassemia
--immune deficiencyimmune deficiency
--storage diseases (Gaucherstorage diseases (Gaucher((
--Bone marrow dysfunction (aplastic anemiaBone marrow dysfunction (aplastic anemia((
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
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
39
T cellsT cells
causecause
GVHDGVHD
GVHD mediated by donor T cellsGVHD mediated by donor T cells
following BMTfollowing BMT
IncidenceIncidence OnsetOnset ManifestationsManifestations
AcuteAcute 50-80%50-80% >>100100
daysdays
Skin, liver, GISkin, liver, GI,,
Immune dysfunctionImmune dysfunction
ChronicChronic 25-50%25-50% <<100100
daysdays
Multi-systemicMulti-systemic
autoimmuneautoimmune
syndromesyndrome
33
Mild aGVHDMild aGVHD
34
Severe aGVHDSevere aGVHD
GI aGVHD (endoscopic capsule)GI aGVHD (endoscopic capsule)
aphtous lesionsaphtous lesions
Oral cGVHDOral cGVHD
Treatment of GVHDTreatment of GVHD
 Prevention – CSA, tacrolimus, MTXPrevention – CSA, tacrolimus, MTX
 Treatment –Treatment –
 High dose steroidsHigh dose steroids
 ATGATG
 CyclophosphamideCyclophosphamide
 Intra-arterial treatmentIntra-arterial treatment
 ThalidomideThalidomide
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
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
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
Stem cell plasticityStem cell plasticity
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

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Bone marrow transplantation

  • 1. Bone MarrowBone Marrow TransplantationTransplantation Marcelo dos SantosMarcelo dos Santos B.Med.Lab.ScB.Med.Lab.Sc..
  • 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
  • 6. Autologous BMTAutologous BMT IndicationsIndications:: LeukemiaLeukemia)?()?( Aggressive LymphomaAggressive Lymphoma Curative IntentCurative Intent HodgkinHodgkin’’s diseases disease Indolent LymphomaIndolent Lymphoma Multiple MyelomaMultiple Myeloma SupportiveSupportive Intent
  • 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
  • 9. Allogeneic BMTAllogeneic BMT  Efficacy based onEfficacy based on Graft versus TumorGraft versus Tumor effecteffect
  • 10. 47 Allogeneic lymphocytes attackAllogeneic lymphocytes attack a blasta blast
  • 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
  • 17. MUDMUD UCBTUCBT MismatchedMismatched familyfamily PROsPROs • No TCDNo TCD • GVLGVL • TimeTime • Less GVHDLess GVHD • TimeTime • Less GVHDLess GVHD • Post SCTPost SCT cell therapycell therapy • FastFast engraftmentengraftment CONsCONs • TimeTime • CostCost • GVHDGVHD • infectionsinfections • Post SCTPost SCT cell therapycell therapy • CostCost • InfectionsInfections • ReducedReduced GVLGVL • SlowSlow engraftmentengraftment • Post SCTPost SCT cell therapycell therapy • MandatoryMandatory TCDTCD • Graft lossGraft loss • InfectionsInfections • ReducedReduced GVLGVL
  • 18. Allogeneic BMTAllogeneic BMT Indications for allogeneic BMTIndications for allogeneic BMT:: --Malignant diseases (leukemia, lymphoma,Malignant diseases (leukemia, lymphoma, renalrenal cell carcinomacell carcinoma(( --Non-malignant hereditary diseasesNon-malignant hereditary diseases:: --thalassemiathalassemia --immune deficiencyimmune deficiency --storage diseases (Gaucherstorage diseases (Gaucher(( --Bone marrow dysfunction (aplastic anemiaBone marrow dysfunction (aplastic anemia((
  • 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
  • 22. GVHD mediated by donor T cellsGVHD mediated by donor T cells following BMTfollowing BMT IncidenceIncidence OnsetOnset ManifestationsManifestations AcuteAcute 50-80%50-80% >>100100 daysdays Skin, liver, GISkin, liver, GI,, Immune dysfunctionImmune dysfunction ChronicChronic 25-50%25-50% <<100100 daysdays Multi-systemicMulti-systemic autoimmuneautoimmune syndromesyndrome
  • 25. GI aGVHD (endoscopic capsule)GI aGVHD (endoscopic capsule) aphtous lesionsaphtous lesions
  • 27. Treatment of GVHDTreatment of GVHD  Prevention – CSA, tacrolimus, MTXPrevention – CSA, tacrolimus, MTX  Treatment –Treatment –  High dose steroidsHigh dose steroids  ATGATG  CyclophosphamideCyclophosphamide  Intra-arterial treatmentIntra-arterial treatment  ThalidomideThalidomide
  • 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
  • 31. Stem cell plasticityStem cell plasticity
  • 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