basics of stem cell transplant

8/8/2019 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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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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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



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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



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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



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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



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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



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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



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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


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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


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



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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


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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



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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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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




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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)




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HaploidenticalHaploidentical

TransplantsTransplants Parent, sibling or childParent, sibling or child

High rate of engraftment failureHigh rate of engraftment failure

GVHDGVHD



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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



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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



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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



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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



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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



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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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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


hematologic malignancies. Manual of Clinical Hematology, 3

rd

edition2002:399-409


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DelayedDelayed

Chronic GVHDChronic GVHD

Scleroderma or Sjogrens syndromeScleroderma or Sjogrens syndrome

BronchiolitisBronchiolitis

KeratoconjunctivitisKeratoconjunctivitis

MalabsorptionMalabsorption

CholestasisCholestasis

Esophageal strictureEsophageal stricture



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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


hematologic malignancies. Manual of Clinical Hematology, 3

rd

edition2002:399-409


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basics of stem cell transplant

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