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Paediatric Haemopoietic Pit/StCllProgenitor/Stem … · Paediatric Haemopoietic...
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Paediatric Haemopoietic P it /St C llProgenitor/Stem Cell TransplantationTransplantation
Karin Tiedemann 2010
Definitions
Autologous HPC TransplantHPC harvested from patient; cryopreserved, reinfused after high dose chemo/irradiation
Syngeneic HPC Transplantdonor genotypically identical to patient (identical twin)
Allogeneic HPC TransplantAllogeneic HPC Transplantdonor not genetically identical to patientmatched sibling/family mismatch/unrelated donormatched sibling/family mismatch/unrelated donor
Transplant activity worldwideTransplant activity worldwide19801980--20092009
35,000Autologous
Allogeneic
25 000
30,000
spla
nts
20,000
25,000
Tran 15,000
10,000
'80 '81 '82 '83 '84 '85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04 '05 '06 '07 '08 '09
5,000
0
SUM10_3.pptSlide 3
'80 '81 '82 '83 '84 '85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04 '05 '06 '07 '08 '09
Allogeneic Haemopoietic Stem CellAllogeneic Haemopoietic Stem Cell Transplantation
Replacement of recipient haemopoietic progenitor cells (HPC) by donor HPCprogenitor cells (HPC) by donor HPCUnique organ transplant
Donor tissue is regenerativeDonor tissue is regenerative Both recipient and donor cells may be immune-competentimmune-competent
Recipient lymphocytes mediate graft rejectionDonor lymphocytes mediate graft-versus-hostDonor lymphocytes mediate graft versus host disease (GVHD) and graft vs leukaemia effect
Haemopoietic Progenitor Cell SourcesHaemopoietic Progenitor Cell Sources
BM PB (Mobilised with G-CSF+/- chemo)
Cord BloodAll may be either
AutologousAutologousAllogeneic
RelatedRelatedUnrelated
HPC ProcurementBM Harvest
GAMultiple BM aspirates from iliac spines/crests
PBSCG CSF MobilisationG-CSF Mobilisation
Bone painSplenomegalyHi h i ld f CD34 ll l i l ibl iHigher yield of CD34+ cells, multiple returns possible in Auto setting
Insertion of large gauge cannulae (high flow rates)peripheral in adultsCVC , GA in paeds
Leukapheresis
HPC ProcurementCord Blood
N vaginal delivery/ Caesarian sectionCord clampedCord cleansedUmbilical vein cannulatedGravity flow into blood collection bag/CPD
l bTransport to processing laboratoryQuality control
TNC, TLC, CD34+ cells, virologyTissue TypingTissue Typing
Volume/red cell reductionAddition of cryoprotectant – DMSORate controlled freeze to -1960Ca e co o ed ee e o 96 CStorage in N2 vapour phaseRegistry Listing
Donor – Recipient Matching
HLA ( Human Leukocyte Antigen) SystemControlled by genes located on short arm Ch 6HLA loci are part of the genetic region known as the MajorHLA loci are part of the genetic region known as the Major Histocompatibility Complex (MHC)MHC molecules control immune response – recognition of self and non selfG d f ti d ll f (S l )Genes code for antigens expressed on cell surfaces (Serology)Each gene is highly polymorphic (allelic differences) DNA sequencing)Ethnic differences in antigen and allele frequencies ie B 44:04Ethnic differences in antigen and allele frequencies ie B 44:04Each parent contributes a haplotype of 3 Class 1 (A, B, C) antigens and 3 Class II (DR, DQ, DP) antigensClose matching between recipient and HPC donor is important for transplant outcome
6/01/2011
transplant outcomePermissive mismatching when CB is donor source
Donor – Recipient Matching
HLA systemEach individual will have 2 antigens/alleles at each g /locus (A, B, C, DR, DQ, DP ) Haplotype
Maternal Haplotype
A1 B4401C3 DR4 DQ3 DP1
Paternal HaplotypeA2 C8 B4403 DR3 DQ7 DP2A2 C8 B4403 DR3 DQ7 DP2
Donor Selection -HLA Inheritance
Maternal Haplotypes Paternal Haplotypes
AB CD
AC AD BC BDAC AD BC BDChildren
Donor Identification
Matched Sib (1;4 chance of match) Best donor!MM related donor - extended family searchMM related donor - extended family search
Search side of family with unusual haplotype/unique antigengCheck for consanguinity and sibs partnering sibs
Unrelated donorVolunteer BM donor Registries - BMDWW
Greater 14 x106 BM/PBSC donors listed
C d Bl d B kCord Blood BanksApprox 435,000 CB units banked
HLA-A, -B & -DR Serologically Matched Pairsb f ll l i t h HLA A B C & DRnumber of allele mismatches HLA-A, -B, -C & -DR
90%
100%
90%
100%
70%
80%
90%
Su 70%
80%
90%
1 mismatched locus (n = 394)0 mismatched loci (n = 791)
2 mismatched loci (n = 172)
40%
50%
60%urviv 40%
50%
60%( )
3+ mismatched loci (n = 65)
20%
30%
40%val
20%
30%
40%
0 0001
0%
10%
0 1 2 3 4 5 6 7 8 90%
10%P-value < 0.0001
0 1 2 3 4 5 6 7 8 9Years After Transplant
Allo BM vs PBSCPBSC lead to more rapid engraftment
N> 0.5x109/L 2-3 days earlierPlatelet independence (>20x109/L) D15 vs D20
Incidence of AGVHD higher for PBSCIncidence of CGVHD higher for PBSCIncreased GVL effect for PBSC (May be useful ( yin advanced leukaemia)Concern re use G-CSF in healthy donors / Children- ? Risk of induction leukaemia
CB vs UDBMReadily available source of HPC, otherwise discarded No donor procedureB tt th i i f HLA tBetter ethnic mix of HLA types
More rapidly available (stored in liquid/vapour N2)More rapidly available (stored in liquid/vapour N2)Important in rapidly progressive diseases – Relapsed ALL
Immunologic immaturityCrossing of HLA barriers > chance of finding donorCrossing of HLA barriers, > chance of finding donorLess GvHD (Advantage in non malignant disease)
No decrease in GvL effect
Cord blood - Disadvantages
Fixed volumeLi it d f it llLimited no. of progenitor cells ? Adequacy of cell dose for larger patients
Delayed engraftmentDelayed Immune reconstitutionyInfection (viral reactivation in recipient)
Potential genetic disease transmissionPotential genetic disease transmission
Changing donor source
’85-89 ’90-94 ’95-00 ‘01-04 ’05-09
MSib BM
21 38 38 34 32
SibCB 0 3 4 3 2SibCB 0 3 4 3 2
MMR 5 12 16 5 8
UDBM 0 1 35 24 7
UDCB 0 0 5 27 49
Conditions treatable with HSCTConditions treatable with HSCT
Conditions Treatable by HPCConditions Treatable by HPC Transplant - Non Malignant
Immune DeficienciesBone Marrow Failure Syndromesy
Single lineage Pure rbc aplasia, CAMT, Kostman Syndrome
Trilineage (SAA FA)Trilineage (SAA, FA)Genetic defects of Hb production
ThalassaemiasThalassaemiasHaemoglobinopathiesCongenital Dyserythropoietic Anaemias
Inherited Metabolic Disorders
Immune Deficiency Disorders
SCID/CID (T and B cell deficiencies)Non SCID PID
Wiscott Aldrich SyndromeDi George SyndromeAtaxia Telangiectasia
Disorders of immune dysregulationFamilial HLHXLP
Defects of phagocyte number/functionChronic Granulomatous Disease Severe Congenital NPA
6/01/2011
LAD-1
‘Other’ Genetic Disorders affectingOther Genetic Disorders affecting haemopoietic lineages
Abnormal Cellular Production/ FunctionRed Cells
β thalassaemia major, βα thalassaemia (1-4 gene deletion/ mutation) Sickle cell diseaseCongenital dyserythropoietic anaemia
Osteoclasts (monocyte derived)
6/01/2011
Malignant Osteopetrosis
Genetic DisordersInherited Metabolic Disorders (Enzyme deficiencies)
MucopolysaccharidosesHurlers Syndrome ( MPS I)Marateaux Lamy Syndrome ( MPS VI)Marateaux Lamy Syndrome ( MPS VI)
LeukodystrophiesCerebral X- linked AdrenoleukodystrophyMetachromatic leukodystrophy - ‘ Juvenile onset’Globoid cell dystrophy
6/01/2011
Malignant Conditions Treatable byMalignant Conditions Treatable by HSC Transplant
ALL/NHLVHR, CR1,CR2
AML/MDS/MDS, untreatedHR, CR1,CR2
Ph+ CMLJMML
T l t I di ti RCHTransplant Indications RCH
Time period1985-2009
ALL/NHL 152 AML/MDS 82 MalignancyCML 10 69%JMML 12SAA/FA 29/8SAA/FA 29/8SCID 27Non SCID ID 21Non SCID ID 21Other 31
Recipient Evaluation
IssuesExpected disease consequencesQuality of standard medical care availableBurden of medical careQuality of lifeChemosensitivity of Malignant diseaseType of donor availableType of donor available
Risk AssessmentDisease vs potential TRMDisease vs potential TRM
Recipient selection
Disease status should allow ‘reasonable’ chance of successful outcome from HPCT
Acute leukaemia/lymphoma in remission/responsiveAcute leukaemia/lymphoma – in remission/responsiveOrgan function normal/ minimally abnormal
RespiratoryCardiacCardiacRenalNeurological
Infection ControlledInfection ControlledBacterialFungalMycobacteriaMycobacteriaViral
Pre Transplant Conditioning
AimsDisease eradication
MalignancyImmunosuppression/ Engraftment
MalignancyMalignancyNon Malignant disorders
Conditioning Regimensil (SC )Nil (SCID)
MyeloablativeChemotherapy +/- TBI +/- ATG
N l bl ti I i d d I t itNon myeloablative, Immunosuppressive, reduced IntensityFludarabine, ATG + Cy / Melphalan /Bu/ Low dose TBI
The Transplant
HSC infusion (IV via CVC)Cryopreserved (CB)y p ( )
Thaw +/- WashFresh Product (BM/PBSC)+/- Manipulation
Volume reductionRed cell depletion (Major ABO MM)Red cell depletion (Major ABO MM)plasma depletion (Minor ABO MM) CD34+ selection (T/B cell depletion) T cell depletion
The Transplant Course
WCC
Transfusion SupportPlatelets
WCCAntibiotics
AGVHD
TBIChemo
VOD AGVHD
BM infusion
7 14
14 21 28 35Days post transplant
GVHD Prophylaxis
Post Transplant Care
Acute chemo-radiation toxicityMarrow Aplasia (18-28D)MucositisMucositis
Oral, oesophageal, lower GIDiarrhoeaSkin toxicity
TBI Et id Thi tTBI, Etoposide, ThiotepaSupportive Care
Blood products (Think of both recipient and donor ABO, Rh groups) May be Major/Minor ABO MMy j /
Antibiotics, antifungalsNutritional support
EngraftmentNeutrophils > 0 5x109/lNeutrophils > 0.5x109/lPlatelets >20x109/l sustained >7D post platelet transfusion
Hepatic Veno-occlusive Disease
‘Sinusoidal Obstruction Syndrome’Onset usually< 21 Days post BMTDi ti C it i ( B lti / M difi d S ttl )Diagnostic Criteria ( Baltimore/ Modified Seattle)
Obstructive Jaundice, Wt gain (2-5%), T d h t lTender hepatomegalyAscites,
Risk factorsAll i BMT> t lAllogeneic BMT> autologous Prior liver diseasePrior MyelotargChemotherapy (Cy,Bu, Melphalan)TBI
Pathology of VODInjury to endothelial cells of sinusoidsExtravasation of rbc into subendothelial spaceO d d thi k i f ll f t lOedema and thickening of wall of central venulesNarrowing of venular lumenNarrowing of venular lumenIncreased resistance to blood flow from portal system to hepatic veinH i iHepatic congestionHepatocyte injury and deathThrombus rarely observed in venules orThrombus rarely observed in venules or sinusoids.
Histopathology of VOD
Disease SeverityMild
No therapy required, recovery D 100 mortality 9%y
ModerateTherapy required, recoverD 100 mortality 23%y
SeverePersistent VOD at D100, death from VODMortality 98%y
Predictors of severityMaximum Bilirubin < 155mmol/l 5% mort, >255mmol/l, mort 81%Encephalopathy -100% mortalityHaemodialysis -14% survival
Prophylaxis against VODUrsodeoxycholic Acid
possible benefit on overall hepatic toxicityPGE1
vasodilator, cytoprotective effect on endothelium – toxic, no benefitATIII
no reduction in incidence of VODLow dose continuous infusion HeparinLow dose continuous infusion Heparin
Benefit not proven but single R study showed benefit. Low incidence toxicity
Defibrotide (Novel polydeoxribonucleotide -, no intrinsic anticoag lant acti it )anticoagulant activity)
Marked reduction in incidence/severity of VOD in small , non randomised studies. R study now confirmed risk reduction by 40% when used
h l ti llprophylactically
Treatment of VODSupportive care
Fluid restriction, diuretics, plateletsCorrection of coagulopathy
Specific therapyDefibrotide – 42% survival in severe VODRecombinant tPA – ‘unacceptable’ incidence of bleeding problems but up to 45% response inbleeding problems but up to 45% response in severe VODLiver transplantp
GVHD
Target OrgansSkinSkin GITLiverLiver
OnsetAGVHD D12 D100AGVHD D12-D100CGVHD >D100
GVHD – Risk FactorsHLA mismatching
Greater the degree of HLA MM the higher the risk of acute and chronic GVHDacute and chronic GVHD
Gender of donorFemale donor, male recipientFemale (previous preg) to female recipient
AgeYounger patients lower incidence and severity ofYounger patients, lower incidence and severity of both acute and chronic GVHD
Stem cell productCB < BM < PBSCCB < BM < PBSCT cell dose
AGVHD - Mechanism
Host tissue damage (Drugs, XRT, Viruses)Antigen exposureCytokine production
TNFα IL 1TNFα, IL-1
Donor Lymphocyte stimulationHost Ag’sHost Ag s Cytokine stimulation
Cytokine stormyIFN gamma, IL-2
AGVHD - Onset D12-100
Skin Rash - patchy and limited, to generalised erythroderma p y , g ywith bullae formation, desquamation
GITDiarrhoea, electroyte and fluid disturbanceVomiting,ileusAbdominal painBleeding
LiverJaundice, enzyme disturbance
AGVHD Overall Grade
Grade Skin GIT Liver
0 - - -
1 M P rash involving1 M-P rash involving up to 50% body
- -
2 >25% MP rash (++) 10-15ml/kg/d Bi 34 -53umol/l2generalised erythroderma (+++)
Persist. nauseaBi 34 53umol/l
3 ++ - ++++ >16ml/kg/d >53umol/l3 ++ ++++ (bullous formation)
/ g/Abdo pain/ileus
/
4 As for 3, with decreased performance
Acute Graft versus Host Disease
ProphylaxisCSA/MTXT-Cell Depletion
CD34 SelectionIn vitro T depletion Anti CD3 AbIn vitro T depletion – Anti CD3 AbIn vivo T depletion - Campath
TreatmentTreatmentSteroids, Cyclosporin, Tacrolimus, MMFATGMonoclonal Ab’sExtra corporeal photopheresis
Acute GVHD
100100--day mortality after day mortality after HLAHLA--identical sibling transplantationidentical sibling transplantationHLAHLA--identical sibling transplantationidentical sibling transplantation
20072007--20082008
100
80
Early Disease
Intermediate Disease
Advance Disease
Chronic Phase
ality,
% 60
Accelerated Phase
Blast Phase
Other
Mort
a
40
2020
0AML CML MDS/MPS I ALL A l i
SUM10_20.pptSlide 18
AML CML MDS/MPS Immune Deficiency
ALL AplasticAnemia
100100--day mortality after day mortality after unrelated donor transplantationunrelated donor transplantationunrelated donor transplantationunrelated donor transplantation
20072007--20082008
100
80
Early Disease
Intermediate Disease
Advance Disease
Chronic Phase
ality,
% 60
Accelerated Phase
Blast Phase
Other
Mort
a
40
2020
0AML CML MDS/MPS I ALL A l i
SUM10_21.pptSlide 19
AML CML MDS/MPS Immune Deficiency
ALL AplasticAnemia
Causes of death Causes of death after transplantations after transplantations
IPn* (1%)Primary Disease (73%)
AutologousAutologous
after transplantations after transplantations done in 2003done in 2003--20082008
Infection (5%)
Organ Failure (4%)
(73%)
Primary Disease (43%)
Other Cause (17%)
HLAHLA--identical siblingidentical sibling
GVHD (10%)(43%)
IPn* (3%) Unrelated donorUnrelated donorPrimary Disease
(35%)
IPn* (5%)
GVHD (12%)Infection(14%)
Infection (17%)
( )
Other (22%)Organ Failure (8%)
SUM10_22.pptSlide 20
Other Cause(19%)
Organ Failure (12%)*IPn = Idiopathic pneumonia syndrome
Chronic GVHD
Risk FactorsRisk FactorsHLA MMPre existing AGVHDe e st g GHSV, VZV infectionAge of donor: Adult > ChildgDonor Source: PBSC>BM>CB
CGVHD – Clinical Manifestations
‘Autoimmune’ like disorderLimited CGVHD
Skin or liver involvement only or bothSkin or liver involvement only, or both
Extensive CGVHDOthe o gan in ol ementOther organ involvement
Chronic GVHD
Onset > Day 100Target OrgansTarget Organs
Skin (pigment, moisture, elasticity, )
Joints ( effusion, stiffness,contracture)
GIT (malabsorption, stricture)
Liver (chronic change to cirrhosis)
Conjunctivae (d i d )Conjunctivae (dry, sicca syndrome)
Mucosal surfaces (dry,ulcers,lichen planus)
Bronchial tree ( bronchiolitis obliterans)( )
Chronic GVHD
Chronic GVHD
Chronic CGVHD
TreatmentCSA Tacrolimus Prednisolone ATGCSA, Tacrolimus, Prednisolone, ATG, AzathiaprineThalidomideThalidomidePUVAECPECP
Immune reconstitution
Donor typeDonor typeMsib PBSC/ BM > MUD> UDCB
G ft M i l tiGraft ManipulationT cell replete > T cell depleted
CGVHDImmunosuppressive therapy
Important milestonesCessation of GVHD prophylaxis
Decreased immunosuppressionDecreased risk of relapseIncreased risk of CGVHD
Early as Possible for Malignant Disease (1-6months post Tx)M sib donor earlier than matched UD earlier than MMUDM sib donor, earlier than matched UD, earlier than MMUDYoung children earlier than older patients (increased risk CGVHD) Delay if severe AGVHD
Later for patients with non malignant disease no benefit from CGVHDno GVL effectrisk of graft rejectionrisk of graft rejection
Return to school (4-12M post Tx)
Post Tx Re-immunisation
Full re-immunisation requiredInactivated vaccines 6-12M post transplant, timing p p , gdependent on B cell recovery
Prevenar, Fluvax from 6 monthsDPT inactivated polio Haemophilus influenzae HBvaxDPT, inactivated polio, Haemophilus influenzae, HBvax, meningococcal vaccine from 12months
Annual Influenza vaccineLive vaccines
Off all immunosuppressionRecovering cellular immunityRecovering cellular immunityGenerally not before 2 yrs post Tx
Relapse Risk post BMTDiagnosisStage of disease at time of transplantStage of disease at time of transplant
CR1,CR2, MRD, Relapse
G ftGraft sourceT cell depletionType/ duration of post graft immunosuppressionpp
Survival
DiseaseMalignantMalignantNon Malignant
Donor sourceDonor sourceAgeStage of disease at time of transplant
Probability of survival after allogeneic Probability of survival after allogeneic transplant for severe aplastic anemia transplant for severe aplastic anemia transplant for severe aplastic anemia, transplant for severe aplastic anemia,
by donor type and age, 1998by donor type and age, 1998--20082008
100100
HLA-matched sibling, ≤20 y (N=1,388)
HLA-matched sibling, >20 y (N=1,408)80
90
80
90
al,
%
Unrelated, ≤20 y (N=562)
Unrelated, >20 y (N=532)
60
50
70
60
50
70
of
Surv
iva
20
40
30
20
40
30
robab
ility
30
20
10
0
20
10
Pr
P < 0.0001
Years
0 2 61 3 4 5
SUM10_48.pptSlide 41
OneOne--year survival after year survival after myeloablativemyeloablativeconditioning for acute leukemias in any remission conditioning for acute leukemias in any remission
phase, CML or MDS, age phase, CML or MDS, age <<50 years, by year of 50 years, by year of transplant and graft source, 1988transplant and graft source, 1988--20082008
100
%
Sibling Donor
Unrelated Donor
80
Surv
ival
,
60
One-
Year
40
20
1988 90 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
20
0
SUM10_18.pptSlide 16
1988-90 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Probability of survival after HLAProbability of survival after HLA--matched matched sibling donor transplant for ALL sibling donor transplant for ALL sibling donor transplant for ALL, sibling donor transplant for ALL,
age age <<20 years, by disease status, 199820 years, by disease status, 1998--20082008
100100
80
90
80
90
al,
%
Early (N=915)
60
50
70
60
50
70
of
Surv
iva
Intermediate (N=1,313)
20
40
30
20
40
30
robab
ility
3
Advanced (N=243)
0
20
10
0
20
10
Pr
P < 0.0001
Years
0 2 61 3 4 5
SUM10_42.pptSlide 35
Probability of survival after unrelated donor Probability of survival after unrelated donor transplant for ALL, age transplant for ALL, age <<20 years, 20 years, p , gp , g y ,y ,
by disease status, 1998by disease status, 1998--20082008
100100
80
90
80
90
al,
%
Early (N=831) 60
50
70
60
50
70
of
Surv
iva
Intermediate (N=2,041)
20
40
30
20
40
30
robab
ility
3
Advanced (N=340)
0
20
10
0
20
10
Pr
P < 0.0001
Years
0 2 61 3 4 5
SUM10_43.pptSlide 36
Probability of survival after HLAProbability of survival after HLA--matched matched sibling donor transplant for AML age sibling donor transplant for AML age <<20 years 20 years sibling donor transplant for AML, age sibling donor transplant for AML, age <<20 years, 20 years,
by disease status, 1998by disease status, 1998--20082008
100 100
80
90
80
90
al,
%
Early (N=1,384)
Intermediate (N=285)
60
50
70
60
50
70
of
Surv
iva
Advanced (N=309)
20
40
30
20
40
30
robab
ility
30
20
10
0
20
10
Pr
P < 0.0001
Years
0 2 61 3 4 5
SUM09_34.pptSlide 28
Probability of survival after unrelated donor Probability of survival after unrelated donor transplant for AML transplant for AML transplant for AML, transplant for AML,
by disease status, 1998by disease status, 1998--20082008
100 100
80
90
80
90
al,
%
Early (N=3,658)60
50
70
60
50
70
of
Surv
iva
Intermediate (N=2,774)
20
40
30
20
40
30
robab
ility
3
Advanced (N=3,242)
0
20
10
0
20
10
Pr
P < 0.0001
Years
0 2 61 3 4 5
SUM10_33.pptSlide 27
Late Effects of BMTChemotherapy TBI
Growth +/- +Cataracts +/- +Infertility + +Sex hormone secretion +/- +/-Thyroid hormone - +/-Cognitive Function +/- +/-(Age / Underlying Disease Dependent)
Ri k f liRisk of malignancy + +
SummaryHSCT offers a chance of cure to manyRisks versus benefits must be weighedgLong term surveillance for late effects of therapypyQuality of life may be compromised post Tx
GVHD, BO
Survival & QOL may increase markedlyie ALL, Hurlers Syndrome, SAA