paediatric haemopoietic pit/stcllprogenitor/stem … · paediatric haemopoietic...

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


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%)


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 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


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


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


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


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


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,


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


Probability of survival after unrelated donor Probability of survival after unrelated donor transplant for AML transplant for AML transplant for AML, transplant for AML,


100 100

80

90

80

90

al,

%

Early (N=3,658)60

50

70

60

50

70

of

Surv

iva


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


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

paediatric haemopoietic pit/stcllprogenitor/stem … · paediatric haemopoietic...

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