basics of stem cell transplant
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Basics of Stem CellBasics of Stem Cell
TransplantTransplant
Tamila KindwallTamila Kindwall--Keller, D.O.Keller, D.O.
August 18, 2008August 18, 2008
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Copyright 2005 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2005;2005:101401
Figure 1. Scanning under low power reveals a heterogenous population of cells
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BackgroundBackground
First successful transplantsFirst successful transplantslatelate1960s1960s
30,00030,000--40,000 transplants performed40,000 transplants performedyearly worldwideyearly worldwide
>20,000 patients have survived >5>20,000 patients have survived >5
yearsyears
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd
edition2002:399-409
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BackgroundBackground
Hematopoietic stem cell transplantationHematopoietic stem cell transplantation
Intravenous infusion of autologous or allogeneicIntravenous infusion of autologous or allogeneic
stem cellsstem cells Collected from bone marrow, peripheral blood orCollected from bone marrow, peripheral blood or
umbilical cord bloodumbilical cord blood
ReRe--establish hematopoietic function in patientsestablish hematopoietic function in patientswith damaged/defective bone marrow orwith damaged/defective bone marrow orimmune systemsimmune systems
Potentially curative for a wide variety ofPotentially curative for a wide variety ofdisordersdisorders
Lazarus HM. Autologous and allogeneic transplantation procedures forhematologic malignancies. Manual of Clinical Hematology, 3rd edition
2002:399-409
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Graft SourcesGraft Sources
Allogeneic: from another personAllogeneic: from another person
Syngeneic: from an identical twinSyngeneic: from an identical twinAutologous: from the patientAutologous: from the patient
Choice of graft is based on diseaseChoice of graft is based on diseasetype, patient condition, donortype, patient condition, donorcompatibility and healthcompatibility and health
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Graft SourcesGraft Sources
Autologous TransplantAutologous Transplant
No evidence of disease in the blood orNo evidence of disease in the blood orbone marrowbone marrow
Transplant related mortality (TRM) lowestTransplant related mortality (TRM) lowestwith autos (
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Graft SourcesGraft Sources
Allogeneic TransplantsAllogeneic Transplants
High TRM (30High TRM (30--50%)50%)
Lower relapse rates due to graft versus tumorLower relapse rates due to graft versus tumoreffectseffects
Graft versus host effectsGraft versus host effects
Matched Related Donor (siblings)Matched Related Donor (siblings)
25% chance a sibling will be a match25% chance a sibling will be a match
The more siblings a patient has the betterThe more siblings a patient has the betterchance for a matchchance for a match
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd
edition2002:399-409
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Graft SourcesGraft Sources
Alternative DonorsAlternative Donors
Matched Unrelated Donors (MUD)Matched Unrelated Donors (MUD)
NMDPNMDP Severe GVHDSevere GVHD
Higher TRMHigher TRM
Haploidentical DonorsHaploidentical Donors
F
rom parent, child or siblingF
rom parent, child or sibling Must have many stem cells to overcome risk of graftMust have many stem cells to overcome risk of graft
rejectionrejection
Increased risk of GVHDIncreased risk of GVHD
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd
edition2002:399-409
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HLA TypingHLA Typing
HLA typing became feasible in 1960sHLA typing became feasible in 1960s
Linked on chromosome 6Linked on chromosome 6
Inherited as haplotypesInherited as haplotypes
1 in 4 chance a sibling will be identical1 in 4 chance a sibling will be identical
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-1826.
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HLA MatchingHLA Matching
6/6, 8/8, or 10/106/6, 8/8, or 10/10
HLA loci on chromosome 6HLA loci on chromosome 6
HLAHLA--A, HLAA, HLA--B, HLAB, HLA--C, HLAC, HLA--DR, HLADR, HLA--DQ,DQ,HLAHLA--DPDP
ABO incompatibility is not an exclusionABO incompatibility is not an exclusion
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd
edition2002:399-409
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EligibilityEligibility
Age < 65Age < 65
Autologous, miniAutologous, mini--alloallo
Age < 55Age < 55
Myeloablative allogeneicMyeloablative allogeneic
ExclusionsExclusions
CHF, uncontrolled diabetes mellitus,CHF, uncontrolled diabetes mellitus,active infections, renal insufficiencyactive infections, renal insufficiency
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Indications AutologousIndications Autologous
TransplantTransplant Multiple myelomaMultiple myeloma
NHLNHL
Hodgkins diseaseHodgkins disease
AMLAML
NeuroblastomaNeuroblastoma
Ovarian cancerOvarian cancer GermGerm--cell tumorscell tumors
AutoimmuneAutoimmunedisordersdisorders
AmyloidosisAmyloidosis
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-1826.
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Indications for AllogeneicIndications for Allogeneic
TransplantTransplant AMLAML
ALLALL
CMLCML MDSMDS
MPDMPD
NHLNHL
Hodgkins DiseaseHodgkins Disease
CLLCLL
Multiple myelomaMultiple myeloma
Juvenile CMLJuvenile CML
Aplastic anemiaAplastic anemia
PNHPNH
Fanconis anemiaFanconis anemia
BlackfanBlackfan--DiamondDiamond
Thalessemia majorThalessemia major
Sickle cell anemiaSickle cell anemia
SCIDSCID
WiskottWiskott--AldrichAldrich
Inborn errors ofInborn errors ofmetabolismmetabolism
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-
1826.
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Preparative RegimensPreparative Regimens
MyeloablativeMyeloablative
High doses of chemotherapy +/High doses of chemotherapy +/-- radiationradiation
3 goals3 goals
Eliminate malignancyEliminate malignancy
Immunosuppression to allow engraftmentImmunosuppression to allow engraftment
Decrease graft versus host effectsDecrease graft versus host effects
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd
edition2002:399-409
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-1826.
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Myeloablative RegimensMyeloablative Regimens
Myeloablative RegimensMyeloablative Regimens
Most common regimensMost common regimens
Cyclophosphamide/TBICyclophosphamide/TBI
Busulfan/CyclophosphamideBusulfan/Cyclophosphamide
Stem cells are essential to restoreStem cells are essential to restore
marrow functionmarrow function
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd
edition2002:399-409
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-1826.
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Myeloablative RegimensMyeloablative Regimens
Therapy is based on diseaseTherapy is based on disease
Other drugsOther drugs
Etoposide, BCNU, cytarabine, melphalanEtoposide, BCNU, cytarabine, melphalan
Graft versus leukemia effects inGraft versus leukemia effects inallogeneic donorsallogeneic donors
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-
1826.
Lazarus HM. Autologous and allogeneic transplantation procedures forhematologic malignancies. Manual of Clinical Hematology, 3rd edition2002:399-409
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Preparative RegimensPreparative Regimens
Nonmyeloablative (MiniNonmyeloablative (Mini--allo)allo)
Sufficient immunosuppression to allowSufficient immunosuppression to allow
donor cell engraftmentdonor cell engraftment
Injury to organs less, fewer infections,Injury to organs less, fewer infections,fewer transfusionsfewer transfusions
Higher relapse ratesHigher relapse rates May have mixed chimerismMay have mixed chimerism
Graft versus tumor effectsGraft versus tumor effectsLazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd
edition2002:399-409
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NonNon--myeloablativemyeloablative
RegimensRegimens Nonmyeloablative RegimensNonmyeloablative Regimens
Usually fludarabine basedUsually fludarabine based
ATG is addedATG is added
May be combined with other drugsMay be combined with other drugs
Busulfan, cyclophosphamide, melphalanBusulfan, cyclophosphamide, melphalan
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd
edition2002:399-409
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NonNon--myeloablativemyeloablative
RegimensRegimens Better for slow growing cancersBetter for slow growing cancers
CLL, NHLCLL, NHL
Graft eradicates the cancer not theGraft eradicates the cancer not thechemochemo
High relapse ratesHigh relapse rates
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-
1826.
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Reduced IntensityReduced Intensity
Conditioning RegimensConditioning RegimensAdvantagesAdvantages
Reduction in mortalityReduction in mortality
Reduction in nonReduction in non--relapse mortalityrelapse mortality
Reduced PRBC and platelet transfusionsReduced PRBC and platelet transfusions
Duration of neutropenia reducedDuration of neutropenia reduced
Reduced numbers of bacteremiasReduced numbers of bacteremias Able to give to heavily pretreated patientsAble to give to heavily pretreated patients
Sandmaier BM, Mackinnon S, Childs RW. Reduced intensity conditioningfor allogeneic hematopoietic stem cell transplanation: Current
perspectives. Biol Blood Marrow Transplant. 2007;13:87-97.
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Reduced IntensityReduced Intensity
Conditioning RegimensConditioning Regimens Reduced GVHD compared toReduced GVHD compared to
myeloablativemyeloablative
Late onset acute GVHD occurringLate onset acute GVHD occurringbeyond day 100beyond day 100
Sandmaier BM, Mackinnon S, Childs RW. Reduced intensity conditioningfor allogeneic hematopoietic stem cell transplanation: Current
perspectives. Biol Blood Marrow Transplant. 2007;13:87-97.
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Principals of ConditioningPrincipals of Conditioning
Donor Lymphocyte Infusions (DLI)Donor Lymphocyte Infusions (DLI)
T cells and NK cellsT cells and NK cells
Additional anticancer effectsAdditional anticancer effects
Preventing relapse or eliminating activePreventing relapse or eliminating activediseasedisease
CML and multiple myelomaCML and multiple myeloma
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd
edition2002:399-409
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Umbilical Cord BloodUmbilical Cord Blood
11ststUCB transplant 16 years agoUCB transplant 16 years ago Child with Fanconis anemiaChild with Fanconis anemia
Cell dose is given per recipient weightCell dose is given per recipient weight Lower patient weights the high the cell doseLower patient weights the high the cell dose
2 x 102 x 1077 nucleated cells/kgnucleated cells/kg
1.7 x 101.7 x 1077 CD 34+ cells/kgCD 34+ cells/kg
4/6 match UCB with sufficient cells has a4/6 match UCB with sufficient cells has asimilar outcome to a matched or onesimilar outcome to a matched or oneantigen mismatched MUDantigen mismatched MUD
Chao NJ, Emerson SG, Weinberg KI. Stem cell transplantation (Cord
Blood Transplants). Am Soc Hematol Ed Book. 2004:354-371.
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Umbilical Cord BloodUmbilical Cord Blood
Umbilical Cord BloodUmbilical Cord Blood
CryopreservedCryopreserved
Small number of stem cellsSmall number of stem cells
Higher incidence of engraftment failureHigher incidence of engraftment failure
Using more than one unit in adultsUsing more than one unit in adults
Lower risk of GVHDLower risk of GVHD Degree of matching not as stringentDegree 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.
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Umbilical Cord BloodUmbilical Cord Blood
Lower GVHDLower GVHD
TRM not different than MUDTRM not different than MUD
Can be used with myeloablative orCan be used with myeloablative ornonmyeloablative conditioning (on anonmyeloablative conditioning (on aclinical trial)clinical trial)
Chao NJ, Emerson SG, Weinberg KI. Stem cell transplantation (Cord
Blood Transplants). Am Soc Hematol Ed Book. 2004:354-371.
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HaploidenticalHaploidentical
TransplantsTransplants Parent, sibling or childParent, sibling or child
High rate of engraftment failureHigh rate of engraftment failure
GVHDGVHD
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-1826.
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Collection of Stem CellsCollection of Stem Cells
Bone Marrow HarvestBone Marrow Harvest
General anesthesiaGeneral anesthesia
Equivalent of 50Equivalent of 50--100 bone marrow100 bone marrowbiopsiesbiopsies
Used much less oftenUsed much less often
2 deaths in 8000 collections2 deaths in 8000 collections
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd
edition2002:399-409
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-1826.
-
8/8/2019 Basics of Stem Cell Transplant
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Copyright 2005 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2005;2005:101279
Figure 2. The posterior iliac crests (arrows) are common sites for bone marrow aspiration
and biopsy
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Collection of Stem CellsCollection of Stem Cells
Stem Cell Collection (mobilization)Stem Cell Collection (mobilization)
Stem cells circulate in the bloodStem cells circulate in the blood
Identified by CD34+ by flow cytometryIdentified by CD34+ by flow cytometry Filgrastim, sargramostim, AMD 3100Filgrastim, sargramostim, AMD 3100
Stem cells are collected through an apheresisStem cells are collected through an apheresiscathetercatheter
More cells are collectedMore cells are collected Higher chronic GVHD than bone marrow harvestHigher chronic GVHD than bone marrow harvest
More rapid marrow recoveryMore rapid marrow recovery
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd
edition2002:399-409
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Infusion of Stem CellsInfusion of Stem Cells
Stem cells may be infused fresh withinStem cells may be infused fresh withina few hours of collectiona few hours of collection
May be frozen using DMSOMay be frozen using DMSO Creamed corn or garlic smellCreamed corn or garlic smell
Umbilical cord blood is obtained fromUmbilical cord blood is obtained from
one of the umbilical cord veins andone of the umbilical cord veins andfrozen with an anticoagulant andfrozen with an anticoagulant andnutrient medianutrient media
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd
edition2002:399-409
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Stem Cell ManipulationStem Cell Manipulation
ABO incompatibleABO incompatible Removal of isoagglutinins or RBCsRemoval of isoagglutinins or RBCs
TT--cell depletioncell depletion Reduce incidence of GVHDReduce incidence of GVHD
Increased graft failureIncreased graft failure
Increased relapse ratesIncreased relapse rates
In vitro purgingIn vitro purging Removal of tumor cellsRemoval of tumor cells
Positive selection of CD34+ cellsPositive selection of CD34+ cells
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3rd
edition2002:399-409
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ComplicationsComplications
EarlyEarly
MucositisMucositis
Sinusoidal obstructive syndrome (VOD)Sinusoidal obstructive syndrome (VOD)
Fluid retention, jaundice, hepatomegalyFluid retention, jaundice, hepatomegaly
Transplant related infectionsTransplant related infections
Damage to mouth, gut and skinDamage to mouth, gut and skin Prolonged neutropeniaProlonged neutropenia
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-1826.
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ComplicationsComplications
EarlyEarly
PancytopeniaPancytopenia
PRBC and platelet transfusionsPRBC and platelet transfusions
Broad spectrum antimicrobialsBroad spectrum antimicrobials
Antifungals if prolonged fevers 3Antifungals if prolonged fevers 3--5 days5 days
Lazarus HM. Autologous and allogeneic transplantation procedures forhematologic malignancies. Manual of Clinical Hematology, 3rd edition2002:399-409
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ComplicationsComplications
EarlyEarly Graft RejectionGraft Rejection
Host versus graftHost versus graft Drug injury to marrowDrug injury to marrow
Viral infections: CMV, HHVViral infections: CMV, HHV--6 & 86 & 8
Interstitial PneumonitisInterstitial Pneumonitis
Diffuse alveolar hemorrhageDiffuse alveolar hemorrhage Too few donor stem cellsToo few donor stem cells
ARDS often caused by CMVARDS often caused by CMV
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3
rd
edition2002:399-409
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ComplicationsComplications
DelayedDelayed
Chronic GVHDChronic GVHD
Scleroderma or Sjogrens syndromeScleroderma or Sjogrens syndrome
BronchiolitisBronchiolitis
KeratoconjunctivitisKeratoconjunctivitis
MalabsorptionMalabsorption
CholestasisCholestasis
Esophageal strictureEsophageal stricture
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-1826.
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Late ComplicationsLate Complications
Secondary TumorsSecondary Tumors Acute leukemias, solid tumors, MDSAcute leukemias, solid tumors, MDS Months to years after transplantMonths to years after transplant Increased incidence with TBIIncreased incidence with TBI
Late InfectionsLate Infections Bacterial, viral fungalBacterial, viral fungal Months after transplantMonths after transplant
Associated with GVHDAssociated with GVHD Need repeat vaccinationsNeed repeat vaccinations
Pneumovax, Hep B, Hemophilus influenza b, poliovirus,Pneumovax, Hep B, Hemophilus influenza b, poliovirus,diphtheria/tetanus, fludiphtheria/tetanus, flu
Lazarus HM. Autologous and allogeneic transplantation procedures for
hematologic malignancies. Manual of Clinical Hematology, 3
rd
edition2002:399-409
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