haematopoietic stem cell transplantation in...

HaematopoieticHaematopoietic Stem cell Stem cell transplantation in transplantation in HaemoglobinopathiesHaemoglobinopathies

ESHESH--EBMT training courseEBMT training courseLatimer, 25Latimer, 25--28,2009.28,2009.Eliane GluckmanEliane Gluckman

Epidemiology of Hb Disorders

300,000 -500,000 children are born with Hb disorders annually:

~80% of affected children are born in developing countries

50,000 – 100,000 children with thalassemia major die each year in low and middle income countries

(World Bank 2006, report of a joint WHO – March of Dimes meeting 2006)

3% OF ALL DEATHS OCCUR IN CHILDREN UNDER 5 YEARS OF AGEThese diseases are: Preventable,Treatable, Curable.

Approximately 250 million people, 4.5% of the world population, are heterozygous for a defective globin gene and at least 300,000 lethally affected homozygotes are born annually, approximately equally divided between thalassemias and sickle cell disorders.

Tuzmen S, Schechter AN. Blood Reviews 2001;15:19-29

ΒΒ ThalassemiaThalassemia

Decreased production of red cells and Decreased production of red cells and hemoglobinhemoglobin

A genetic defect in A genetic defect in globin gene globin gene causes decreased production of causes decreased production of proteinprotein

Ref: Ref: ββ--Thalassemia D. Thalassemia D. RundRund and E. and E. RachmilewitzRachmilewitz New Engl J of Med 353:1135, 2005New Engl J of Med 353:1135, 2005

Genetics of Genetics of ββ thalassemiathalassemia

Thalassemia traitThalassemia trait: benign : benign –– One thalassemia gene excess One thalassemia gene excess αα genesgenes

Thalassemia majorThalassemia major: severe disease : severe disease –– Two thalassemia genesTwo thalassemia genes

Thalassemia Thalassemia intermediaintermedia: : mild to severemild to severe–– 2 mutations one is mild with excess 2 mutations one is mild with excess αα globin globin genesgenes

Hemoglobin E ThalassemiaHemoglobin E Thalassemia : mild to severe: mild to severe–– One One ββ genegene carryingcarrying a thalassemia mutation with a a thalassemia mutation with a ββ

globin globin genegene carryingcarrying the point mutation the point mutation encodingencodinghemoglobinhemoglobin EE

Globin synthesis in Globin synthesis in thalassemia (% of normalthalassemia (% of normal))

+ + thalthal -- 30% 30% 100% 100% 0 0 thalthal -- 0 % 0 % 100% 100%

nemianemia due to:due to:•• Decreased Decreased globin synthesisglobin synthesis•• Sustained normal Sustained normal globin synthesisglobin synthesis•• Uncompensated Uncompensated globin synthesisglobin synthesis

Leading to excess Leading to excess globin precipitation globin precipitation -- hemolysishemolysis

Treatment for Treatment for ββThalassemiaThalassemia

Blood transfusionsBlood transfusions: usually monthly: usually monthly Iron chelating agentsIron chelating agents

•• Subcutaneous Subcutaneous DesferalDesferal•• Oral Oral Deferoxamine,Deferiprone,DeferasiroxDeferoxamine,Deferiprone,Deferasirox

•• Endocrine supportEndocrine support•• OsteoporosisOsteoporosis OsteoclastOsteoclast replacement, replacement, VitaminDVitaminD Bone marrow transplantationBone marrow transplantation Experimental approachesExperimental approaches

•• Increase fetal hemoglobin :hydroxyureaIncrease fetal hemoglobin :hydroxyurea•• Gene therapyGene therapy

Survival by Availability of Survival by Availability of Chelation TherapyChelation Therapy

Borgna-Pignatti et al. Haematologica. 2004;89:1187.

30Age (y)

Surv

ival

pro

babi

lity

0 5 20 25

0.25

0

0.50

1.00 1985-97

0.75

15

P<0.00005

1980-84 1975-79

1970-74

1965-69

1960-64

10

(N=1073)

Year of Assessment

Transfusion-Dependent Patients With Thalassemia Major

Prevention of Prevention of HaemoglobinopathiesHaemoglobinopathies

Prenatal ScreeningPrenatal Screening Genetic counselingGenetic counseling Antenatal diagnosis:Antenatal diagnosis:

•• Chorionic villous biopsyChorionic villous biopsy•• AmniocentesisAmniocentesis

•• PGD/IVFPGD/IVF

Indications of HSCT in Indications of HSCT in ThalassemiaThalassemia Definite indicationDefinite indication

–– TransfusionTransfusion--dependent dependent αα or or ββ thalthal; transfusion ; transfusion ––dependentdependent HbEHbE//ββ--thalthal

–– AgeAge<<16 16 yearsyears–– HLA HLA identicalidentical familyfamily donordonor

Candidates Candidates whowho maymay bebe consideredconsidered for HSCTfor HSCT–– TranfusionTranfusion--dependentdependent thalthal major in major in adultsadults 1717--35 35

yearsyears–– Thal Thal relapsingrelapsing afterafter previousprevious HSCTHSCT–– TransfusionTransfusion--dependentdependent SS--ββ°° thalthal–– ThalThal intermediaintermedia

Factors affecting the decision to transplant patients with hemoglobinopathies

1. The expected results of SCT: cure, TRM and the risk of chronic GVHD

2. The long-term effects of SCT3. The age of the patient4. The availability of the donor5. The expected long term survival without SCT based

on transfusion and compliance history and the impact of current treatment on quality of life

6. Prospects for improved management in the future

Risk Classes for BMT in Risk Classes for BMT in ThalassemiaThalassemiaN Engl J Med 1990; 322: 417N Engl J Med 1990; 322: 417--2121

ChelationChelation HepatomegalyHepatomegaly Hepatic FibrosisHepatic Fibrosis

Class 1Class 1 RegularRegular NONO AbsentAbsent

Class 2Class 2 Reg/ IrrReg/ Irr NO/YESNO/YES NO/YESNO/YES

Class 3Class 3 IrregularIrregular YESYES YESYES

0 2 4 6 8 10 12 14 160

0,2

0,4

0,6

0,8

1

Prob

abili

ty

Class 1 Thalassemia (age < 17 years) (n=126)Busulfan 14 mg/kg Cyclophosphamide 200 mg/kg

SURVIVAL

THALASSEMIA-FREE SURVIVAL

NON-REJECTION MORTALITYREJECTION

92%90%

8%3%

YEARS

0 2 4 6 8 10 12 14 160

0,2

0,4

0,6

0,8

1

Prob

abili

tyClass 2: Thalassemia – age <17 years (n=292)

SURVIVAL


NON-REJECTION MORTALITY

REJECTION

87%84%

14%4%

YEARS

Busulfan 14 mg/kg Cyclophosphamide 200 mg/kg

0 2 4 6 8 10 12 140

0.2

0.4

0.6

0.8

1

Prob

abili

ty

SURVIVAL


REJECTION

NON-REJECTION MORTALITY 47%47%

12%

50%

Class 3 Thalassemia ( <17 years) n = 35Busulfan 14 – Cyclophosphamide 200

YEARS

0 2 4 6 8 10 120

0.2

0.4

0.6

0.8

1

Prob

abili

tyClass 3 Thalassemia ( <17 years) (n=122)Class 3 Thalassemia ( <17 years) (n=122)

BU 14 BU 14 –– CyclophosphamideCyclophosphamide 120/160120/160

SURVIVAL


REJECTION


79%

58%

30%18%

YEARSPesaro May 2000

0 2 4 6 8 10 12 140

0.2

0.4

0.6

0.8

1

Prob

abili

tyADULT THALASSEMIA (n=109)

SURVIVAL



REJECTION

66%62%

36%

4%

YEARS

BMT IN THALASSEMIABMT IN THALASSEMIAFFUTURE DIRECTIONS UTURE DIRECTIONS

SpecificSpecific conditioningconditioning regimenregimen for patients for patients with with advancedadvanced disease disease

ReducedReduced intensityintensity or non myeloablative or non myeloablative preparativepreparative regimenregimen: : encouragingencouraging resultsresults?? ??

Induction of persistent chimerism Induction of persistent chimerism Alternative source of Stem cells (cord Alternative source of Stem cells (cord

blood)blood) Alternative Alternative donorsdonors ((matchedmatched unrelated unrelated

donorsdonors 10/10 )10/10 ) Expansion of BMT Expansion of BMT DonorsDonors’’ RegistriesRegistries on on

regionalregional basisbasis PrePre--implantationimplantation diagnosisdiagnosis

HSCT for sickle cell diseaseHSCT for sickle cell disease

Severe recessive genetic disorder resulting from a Severe recessive genetic disorder resulting from a single nucleotide substitution in codon 6 of the single nucleotide substitution in codon 6 of the ββglobin: globin: genegene ββ6 Glu 6 Glu ValVal

In the In the homozygoushomozygous state, state, itit producesproduces abnormalabnormalhemoglobin hemoglobin thatthat isis proneprone to to polymerpolymer formation formation underunder deoxygenateddeoxygenated conditions.conditions.

The The polymerizedpolymerized haemoglobinhaemoglobin leadsleads to to decreaseddecreasedRBC RBC deformabilitydeformability and sickling in end and sickling in end arteriolesarteriolesresultingresulting in in vasoocclusionvasoocclusion and painand pain

It It isis associatedassociated with severe complications: with severe complications: stroke,acutestroke,acute chestchest syndrome and syndrome and recurrentrecurrent painpain

SICKLE CELL DISEASESICKLE CELL DISEASE The median age of survival for female patients The median age of survival for female patients

was 36.3 years and for males, 38.7 years.was 36.3 years and for males, 38.7 years.

Fifty percent of children born with sickle cell Fifty percent of children born with sickle cell anemia during the 21anemia during the 21stst century can expect to century can expect to survive into the fifth decade of life.survive into the fifth decade of life.

This longer life span is accompanied by an This longer life span is accompanied by an increasing number of complications that increasing number of complications that negatively impact their quality of life.negatively impact their quality of life.

Powers et a. Medicine (Baltimore)Powers et a. Medicine (Baltimore)

2005;84:3632005;84:363--376376

Sickle Cell Disease MorbiditySickle Cell Disease Morbidity

Overt and incomplete (silent) cerebral infarction.Overt and incomplete (silent) cerebral infarction. Silent cerebral infarcts result in impaired Silent cerebral infarcts result in impaired

cognitivecognitivefunctioning.functioning.

Children with SCD are at risk educationally Children with SCD are at risk educationally becausebecauseof cognitive and intellectual impairment asof cognitive and intellectual impairment ascompared with siblings or noncompared with siblings or non--affected peers.affected peers.

Nearly half of all patients with sickle cell anemiaNearly half of all patients with sickle cell anemiasuffer brain injury.suffer brain injury.

Psychological complications in sickle cell disease.Psychological complications in sickle cell disease.AnieAnie KA., Br J Haematol. 2005;129:723KA., Br J Haematol. 2005;129:723--99

Opposing Attitudes Regarding Opposing Attitudes Regarding Transplantation in Sickle Cell DiseaseTransplantation in Sickle Cell Disease

Since disease severity cannot be Since disease severity cannot be predicted, transplant only those predicted, transplant only those patients who have developed severe patients who have developed severe complications of the disease are complications of the disease are transplanted because some patients transplanted because some patients will die as a result of transplantation.will die as a result of transplantation.

Early transplantation would prevent Early transplantation would prevent irreversible morbidity and decrease irreversible morbidity and decrease transplanted related complications.transplanted related complications.

Will 50% of patients transplanted at Will 50% of patients transplanted at an early age be dead by age 50?an early age be dead by age 50?

SCD Palliative treatmentSCD Palliative treatment

Pneumococcal vaccines and prevention Pneumococcal vaccines and prevention of infectionsof infections

Pain managementPain management HydroxyureaHydroxyurea Exchange transfusionExchange transfusion

Indications of HSCT in SCDIndications of HSCT in SCD

YoungYoung patients with HLA identical donorspatients with HLA identical donors

1 or more of the following complications1 or more of the following complications–– Stroke without severe cognitive disabilitiesStroke without severe cognitive disabilities–– Stenosis or occlusions on cerebral magnetic resonance angiographStenosis or occlusions on cerebral magnetic resonance angiographyy–– Ischaemic lesions demonstrated by cerebral MRIIschaemic lesions demonstrated by cerebral MRI–– Recurrent vasoRecurrent vaso--occlusive crisis and/or acute chest syndrome and/or priapism occlusive crisis and/or acute chest syndrome and/or priapism

despite hydroxyureadespite hydroxyurea–– Osteonecrosis in multiple jointsOsteonecrosis in multiple joints–– Red cell Red cell immunisationimmunisation with 2 or more antibodieswith 2 or more antibodies

Or with 1 or more severe risk factorsOr with 1 or more severe risk factors–– Abnormal high velocities on transcranial DopplerAbnormal high velocities on transcranial Doppler–– Severe chronic anaemia Hb<7g/dlSevere chronic anaemia Hb<7g/dl–– Tricuspid jet regurgitation >2.5 m/sec on cardiac DopplerTricuspid jet regurgitation >2.5 m/sec on cardiac Doppler

worldwide experience of HSCT in SCDworldwide experience of HSCT in SCD

BelgiumBelgiumVermylenVermylen

USAUSAWaltersWalters

France France BernaudinBernaudin

Patients nPatients n 5050 5050 8787

Median ageMedian age 7.57.5 9.49.4 8.88.8

StrokesStrokes 8%8% 50%50% 40%40%

RejectionRejection 10%10% 10%10% 7%7%

TRMTRM 7%7% 6%6% 7%7%

EFSEFS 82%82% 84%84% 86%86%

A.GVHA.GVH 20%20% 15%15% 86%86%

C.GVHC.GVH 20%20% 12%12% 13%13%

HSCT in Sickle Cell DiseaseHSCT in Sickle Cell Disease 67 patients from 30 centers transplanted 67 patients from 30 centers transplanted

between 1989 and 2002 with matched between 1989 and 2002 with matched sibling donors.sibling donors.

Median age = 10 years; 67% had >10 Median age = 10 years; 67% had >10 transfusions before HSCT.transfusions before HSCT.

Stroke, n= 24; nephropathy, n= 7, acute Stroke, n= 24; nephropathy, n= 7, acute chest syndrome, n=6.chest syndrome, n=6.

Acute GVHD = 10% (grade 3Acute GVHD = 10% (grade 3--4 in 2 4 in 2 patients); chronic GVHD = 22% (limited in patients); chronic GVHD = 22% (limited in 75%).75%).

55--year probability: OS = 97%; DFS = 85%year probability: OS = 97%; DFS = 85%

PanipintoPanipinto et al., (CIBMTR)et al., (CIBMTR)British J HaematolBritish J Haematol

2007;1327:4792007;1327:479--485485

ClinicalClinical resultsresults and and perspectives of allo stem cell perspectives of allo stem cell transplants for patients with transplants for patients with sicklesickle cell diseasecell disease

F Bernaudin and E GluckmanF Bernaudin and E Gluckman

SociSociééttéé FranFranççaise de Greffe de Moelle et aise de Greffe de Moelle et ThThéérapie Cellulairerapie Cellulaire

Blood 110:2749Blood 110:2749--2756, 20072756, 2007

French French experienceexperience 60 Patients60 Patients (11/1988 (11/1988 to 03/2002)to 03/2002)

Multicentric Multicentric studystudy Genoidentical (n=58), Genoidentical (n=58), mismatchmismatch relatedrelated

(n=2)(n=2) Source of cells:Source of cells:

Bone Marrow (n=51), Bone Marrow (n=51), cord blood (n=7), cord blood (n=7), Bone marrow+ cord blood (n=1),Bone marrow+ cord blood (n=1), PeripheralPeripheral Blood (n=1)Blood (n=1)

MedianMedian Age : 8.8Age : 8.8 yearsyears (2.2 to 22 )(2.2 to 22 )–– 3 cases >16 y3 cases >16 y

Indications (60 patients)Indications (60 patients)

CerebralCerebral VasculopathiesVasculopathies n = 26n = 26

–– StrokesStrokes n = 22n = 22

–– Transit. Transit. IschemiaIschemia n = 1n = 1

–– StenosisStenosis n = 3n = 3

VasoVaso--occlusive occlusive crisiscrisis +/+/-- arterialarterial stenosisstenosis n = 25n = 25

Severe anemia Severe anemia ±± stroke n = 9stroke n = 9

OsteonecroisOsteonecrois, non , non respondersresponders to to HydreaHydrea n= 5n= 5

PolyPoly--erythroerythro--alloallo--immunizationimmunization n = 1n = 1

ConditioningConditioning

BU + EDXBU + EDX n = 17n = 17 BU + TLIBU + TLI n = 1n = 1 BU + EDX + ATGBU + EDX + ATG n = 42n = 42

BU 485 mg/m2 (BU 485 mg/m2 (>>16mg/kg)16mg/kg)++

EDX 200 mg/kgEDX 200 mg/kg++

ATG ATG rabbitrabbit 20 mg/kg20 mg/kg

PreventionPrevention of GVHof GVH•• CSA CSA n = 13 n = 13 •• CSA + MTX CSA + MTX n = 47n = 47

EngraftmentEngraftment

59/60 59/60 engraftmentengraftment–– MedianMedian daysdays of neutrophil of neutrophil reocveryreocvery

(PN>500) :(PN>500) : 20 20 daysdays in in bonebone marrow transplantsmarrow transplants 28 28 daysdays in cord blood transplantsin cord blood transplants

1 non1 non--engraftmentengraftmentcord blood (first transplant): non cord blood (first transplant): non

engraftmentengraftment atat dayday 34 , 34 , bonebone marrow marrow (second transplant) with (second transplant) with autologous autologous

reconstitutionreconstitution

Chimerism and rejection Chimerism and rejection

BeforeBefore association with ATG association with ATG –– 4/12 mixed 4/12 mixed chimerachimera

3 rejection3 rejection–– autologous reconstitution (5m, 28m, autologous reconstitution (5m, 28m,

100m)100m)

1 aplasia (2nd transplant)1 aplasia (2nd transplant)

AfterAfter association with ATGassociation with ATG–– 1 non1 non--engraftmentengraftment

Survival : 90% (KaplanSurvival : 90% (Kaplan--Meier, Meier, medianmedian 52 52 monthsmonths))60 patients (02/2002)60 patients (02/2002)

Follow-Up (mois)

2001000

1,00

,90

,80

,70

,60

,50

,40

,30

,20

,10

0,00

Rejection Rejection accordingaccording to use of ATG in the to use of ATG in the conditioningconditioning

Follow-Up (mois)

2001000

1,0

,9

,8

,7

,6

,5

,4

,3

,2

,1

0,0

25%

2%

P (log rank)=0.06

DFS patients DFS patients transplantedtransplanted with ATG, genoidentical with ATG, genoidentical and < 15 and < 15 yearsyears : 88%: 88% (n=33)(n=33)

Follow-Up (mois)

120100806040200

1,00

,90

,80

,70

,60

,50

,40

,30

,20

,10

0,00

Causes of Causes of deathdeath (n = 60)(n = 60)

MedianMedian FollowFollow--up : 52 up : 52 monthsmonths (1(1--159 159 monthsmonths)) 6 6 deathsdeaths

–– Severe GVH (n=4)Severe GVH (n=4) 2 m : 2 m : adenovirusadenovirus 4 m : CMV, 4 m : CMV, pneumocystispneumocystis, aspergillosis, aspergillosis 12 m : 12 m : bronchiolitisbronchiolitis obliteransobliterans 12 m : 12 m : sepsissepsis

–– InntracerebralInntracerebral HemorHemor. (n=1) (. (n=1) (MoyaMoya--moyamoya))–– Non Non engraftementengraftement (n=1): (n=1): sepsissepsis, ARDS, ARDS

Long Term F/U after BMT: CNSLong Term F/U after BMT: CNS(N=55 surviving pts.)(N=55 surviving pts.)

BASELINE > 2 YEARS FOLLOW/UP

30 stroke One stroke 29 stable or improved MRI

9/25 ‘silent’ stroke

No stroke 7/9 studied had stable or improved MRI

16 normal (12 not studied)

No stroke 4 studied had normal MRI

Conclusion 1Conclusion 1

HLA HLA identicalidentical allotransplantallotransplant cancan cure :cure :–– 88% of severe SCD in patients <15 88% of severe SCD in patients <15 yearsyears–– With a With a riskrisk of 10% of of 10% of mortalitymortality ((mainlymainly GVH )GVH )

Addition of ATG Addition of ATG decreaseddecreased the the riskrisk of rejection of rejection fromfrom 25% to 2,4% 25% to 2,4%

Related Cord Blood Transplant in PatientsRelated Cord Blood Transplant in Patientswith Thalassemia and with Thalassemia and SickleSickle Cell diseaseCell disease

F. Locatelli, V. Rocha, W. Reed, F. Bernaudin, M Ertem, S Grafakos,B Brichard, X Li, G. Giorgiani, A Nagler, Lubin BH,

Gluckman E.on behalf of Eurocord - Cord Blood Transplant Group

Related CBT for HemoglobinopathiesRelated CBT for Hemoglobinopathies

44 patients 44 patients transplantedtransplanted fromfrom 06/94 to 06/2001 in 10 countries and 22 06/94 to 06/2001 in 10 countries and 22 transplant centerstransplant centers

MedianMedian ageage : 5 y (1: 5 y (1--20) ; 1 patient > 15 20) ; 1 patient > 15 yearsyears

MedianMedian weightweight :18 kg (9:18 kg (9--45)45)

19 male ; 25 19 male ; 25 femalefemale

MedianMedian followfollow--up time : 24 up time : 24 monthsmonths (3(3--76)76)


ConditioningConditioning

BU + CY:BU + CY: 2626((associatedassociated to ATG/ALG: 18)to ATG/ALG: 18)

BU + CY+ ThiotepaBU + CY+ Thiotepa 1010

BU+Thiotepa + FludarabineBU+Thiotepa + Fludarabine 88

BU + CY+BU + CY+ Fludarabine Fludarabine 11


DonorsDonors

HLA HLA identicalidentical siblings : 41siblings : 41

HLA HLA mismatchedmismatched donorsdonors : 3 (1 HLA: 3 (1 HLA--A A differencedifference))


EngraftmentEngraftment duringduring the first 60 the first 60 daysdays: : n=38n=38

KM KM estimateestimate for neutrophil for neutrophil recoveryrecovery ( ( >>500) : 89%500) : 89%MedianMedian daysdays : 23 (12: 23 (12--60)60)

KM KM estimateestimate for for plateletplatelet recoveryrecovery ( ( >> 20000) : 90%20000) : 90%MedianMedian : 39 (19: 39 (19--92)92)

Non Non engraftmentengraftment atat dayday 60 : 60 : 6 patients6 patients

LateLate graft graft failurefailure : n=2 : n=2 atat dayday +150 and + 165+150 and + 165

Days10 20 30 40 50 60

00.

20.

40.

60.

81.

0

N engraftment44 38

89%

Related CBT for hemoglobinopathies

Neutrophil recovery

91%

9% Grade 0-IGrade II


Acute GVHD

Chronic GVHD

2 /36 patients at riskKM estimate : 6%

(n=40)(n=4)

KM estimate of aGVHD for patients with neutrophils recovery =11%

Days

EFS

0 500 1000 1500 2000 2500

0.0

0.2

0.4

0.6

0.8

1.0

90%

79%

n events

Thalassemia 33 7

Sickle cell disease 11 1

P=0.5

Thalassemia

Sickle cell disease

Sickle cell disease

Related CBT for hemoglobinopathiesEvent free survival according to diagnosis

Days

EFS

0 500 1000 1500 2000 2500

0.0

0.2

0.4

0.6

0.8

1.0

n eventsBuCy 26 7Other 18 1

P=0.07

94%

71%

Related CBT for hemoglobinopathiesEvent free survival according to conditioning

Days

EFS

0 500 1000 1500 2000 2500

0.0

0.2

0.4

0.6

0.8

1.0

nevents

Class I 20 2Class II 13 5

p=0.06

89%

62%Pesaro Class II

Pesaro Class I

Related CBT for ThalassemiaEvent free survival according to Pesaro classification

ConclusionsConclusions

Related CBT for hemoglobinopathies Related CBT for hemoglobinopathies offersoffers a a probabilityprobability of of successsuccesscomparable to comparable to thatthat offeredoffered by BMT and by BMT and isis associatedassociated with with lowerlower riskriskof of bothboth TRM and cGVHD. TRM and cGVHD.

Optimization of transplant strategies could further improve thesOptimization of transplant strategies could further improve these e results. results.

In particular, in view of the lower rate of engraftment associatIn particular, in view of the lower rate of engraftment associated with ed with use of MTX and of the low risk of GVHD in patients given use of MTX and of the low risk of GVHD in patients given transplantation of placental blood, prophylaxis of GVHD includintransplantation of placental blood, prophylaxis of GVHD including this g this drug is contradrug is contra--indicated. indicated.

A preparative regimen consisting of either BU, TT and CY or BU, A preparative regimen consisting of either BU, TT and CY or BU, TT TT

and FLU should be preferred in thalassemia patientsand FLU should be preferred in thalassemia patients..

A MULTICENTRIC COMPARATIVE ANALYSIS OF OUTCOMES OF HLA A MULTICENTRIC COMPARATIVE ANALYSIS OF OUTCOMES OF HLA IDENTICAL RELATED CORD BLOOD AND BONE MARROW IDENTICAL RELATED CORD BLOOD AND BONE MARROW TRANSPLANTATION IN PATIENTS WITH BETATRANSPLANTATION IN PATIENTS WITH BETA--THALASSEMIA OR THALASSEMIA OR SICKLE CELL DISEASESICKLE CELL DISEASE

N.KabbaraN.Kabbara, F. Locatelli, V. Rocha, S. Grafakos , F. Locatelli, V. Rocha, S. Grafakos A.GhavamzadehA.Ghavamzadeh, , I.RobertsI.Roberts, , C.KongC.Kong Li, F. Bernaudin, C. Vermylen, JH Li, F. Bernaudin, C. Vermylen, JH Dalle, J. Stein, R. Wynn, P. Lutz, C. Cordonnier, F. Pinto, E. ADalle, J. Stein, R. Wynn, P. Lutz, C. Cordonnier, F. Pinto, E. Angelucci, ngelucci,

G.SociG.Sociéé, E. Gluckman, M. Walters, E. Gluckman, M. Walters

ASBMT meeting February 15 2008

OBJECTIVES & INCLUSION CRITERIAOBJECTIVES & INCLUSION CRITERIA

Compare outcomes of CBT & BMT from HLA identical sibling in Compare outcomes of CBT & BMT from HLA identical sibling in hemoglobinopathyhemoglobinopathy..

Transplant centers: both type of transplantations have been perfTransplant centers: both type of transplantations have been performed.ormed.

Eurocord data base: (1994Eurocord data base: (1994--2005) 76 patients had either thalassemia major 2005) 76 patients had either thalassemia major or Sickle cell disease.or Sickle cell disease.

13 of 17 centers agreed to participate in the study.13 of 17 centers agreed to participate in the study.


Patients & Methods Patients & Methods

Patients and Disease Patients and Disease BMBMN=389N=389

CBCBN=70N=70

P valueP value

Age, Age, medianmedian ((yearsyears)) 8.1 (0.78.1 (0.7--24)24) 6.1 (26.1 (2--20)20) 0.020.02

Donor Donor ageage, , medianmedian ((yearsyears)) 9 (0.29 (0.2--30)30) NANA

DiseaseDiseaseThalassemiaThalassemiaSCDSCD

259 (67%)259 (67%)130 (33%)130 (33%)

44 (63%)44 (63%)26 (37%)26 (37%)

0.550.55

Indications for ThalassemiaIndications for ThalassemiaPesaro IPesaro IPesaro IIPesaro IIPesaro IIIPesaro III

Indications for SCDIndications for SCDCNS+CNS+CNS CNS --

86 (33%)86 (33%)122 (47%)122 (47%)51 (20%)51 (20%)

57 (56%) 57 (56%) 73 (44%)73 (44%)

26 (61%)26 (61%)15 (35%)15 (35%)

2 (4%)2 (4%)

14 (54%)14 (54%)12 (46%)12 (46%)

<0.01<0.01

0.830.83


Patients & Methods Patients & Methods

Transplant Transplant characteristicscharacteristics

MedianMedian year of transplantationyear of transplantation

BMBMN=389N=389

1999 (941999 (94--05)05)

CBCBN=70N=70

2001 (942001 (94--05)05)

p valuep value

<0.01<0.01

ConditioningConditioning regimensregimens (myeloablative)(myeloablative)BusulfanBusulfan--CytoxanCytoxanBusulfanBusulfan--CytoxanCytoxan--FludaFludaBusulfanBusulfan--ThiotepaThiotepa--FludaFludaBusulfanBusulfan--FludarabineFludarabineBusulfanBusulfan--CytoxanCytoxan--ThiotepaThiotepa

345 (89%)345 (89%)16 (4%)16 (4%)27 (7%)27 (7%)

0000

44 (63%)44 (63%)4 (6%)4 (6%)

14 (20%)14 (20%)3 (4%)3 (4%)5 (7%)5 (7%)

<0.01<0.01

ATG/ ALG/ATG/ ALG/MonoAbMonoAb 259 (67%)259 (67%) 33 (44%)33 (44%) 0.0020.002

NumberNumber of cells of cells infusedinfused 4.1 (0.14.1 (0.1--46)46) 0.39 (0.10.39 (0.1--1.4)1.4) <0.01<0.01

GvHD GvHD prophylaxisprophylaxisMethotrexate Methotrexate basedbasedCsA CsA alonealoneCsA +/CsA +/-- otherother ISISMMFMMF

297 (76%)297 (76%)82 (21%)82 (21%)

385 (99%)385 (99%)00

18 (26%)18 (26%)43 (61%)43 (61%)68 (97%)68 (97%)6 (8,6%)6 (8,6%)

<0.01<0.01<0.01<0.01


BM CBGrade II 46 (12%) 3 (4%)Grage III 29 (7%) 4 (6%)Grade IV 8 (2%) 0

Acute GvHD (II-IV) & cGvHD by graft type

cGvHDBM: 41/355 (12+/-2%)CB: 3/58 (5+/-3%)

20±2%n=83

10±4%n=7CB

BM

p=0.04days

100806040200

1.1

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Overall Survival by graft type

95±1%

96±3%CB (n=70)

BM (n=389)

monthsp=0.92

60544842363024181260

1.1

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

n=18n=18 n=3n=3

GvHDGvHD 88 00

HemorrhageHemorrhage 33 22

Infections Infections 55 00

ToxicitiesToxicities (VOD, (VOD, ARDS, ARDS, SeizuresSeizures)) 22 11

88±2%

81±2%CB (n=70, ev =13)

BM (n=389, ev=47)

p=0.11

months


In multivariate analysis

DiseaseAge at TxYear at Tx

Event free Survival by graft type

60544842363024181260

1.1

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0(Ev= death or autologous reconstitution or transfusion dependency)

SCD (n=156, ev=13)

Thalassemia (n=303, ev=47)

92±2%

84±2%

p=0.04 months


Event free Survival by disease

60544842363024181260

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

ConclusionConclusion

Patients with Thal. or SCD have excellent Patients with Thal. or SCD have excellent outcomeoutcome..

ResultsResults werewere not not statisticallystatistically differentdifferent accordingaccording to to the source of stem cell the source of stem cell usedused..

Cord blood Cord blood isis associatedassociated with with lessless acute GvHD, but acute GvHD, but delayeddelayed neutrophil neutrophil engraftmentengraftment. .

Sibling cord blood banking for Hemoglobinopathies Sibling cord blood banking for Hemoglobinopathies shouldshould bebe encouragedencouraged to to avoidavoid disconfortdisconfort and and risksrisks of of BM BM harvestharvest


HSCT in Sickle Cell DiseaseHSCT in Sickle Cell DiseaseThese data argue for These data argue for early referralearly referral and HCT in sickle cell disease patients and HCT in sickle cell disease patients so that HCT may be performed in younger patients with minimal exso that HCT may be performed in younger patients with minimal exposure posure to red blood cell transfusions.to red blood cell transfusions.Finding a matched adult donor for a patient with sickle cell disFinding a matched adult donor for a patient with sickle cell disease is very ease is very difficultdifficultTherefore, the only hope of satisfying the needs of sickle cell Therefore, the only hope of satisfying the needs of sickle cell disease disease patients is the use of BM or CB from unrelated donors.patients is the use of BM or CB from unrelated donors.

34% of patients with sickle cell disease were willing to accept 34% of patients with sickle cell disease were willing to accept the risk of a the risk of a 20% short20% short--term mortality in exchange for cure. term mortality in exchange for cure.

There was no agreement between the recommendations of health There was no agreement between the recommendations of health care care providers and the risk accepted by patients. providers and the risk accepted by patients.

If the parents of a child with sickle cell anemia want the childIf the parents of a child with sickle cell anemia want the child to be to be transplanted, should access to transplantation be denied?transplanted, should access to transplantation be denied?

At present, the option of transplantation is usually not even prAt present, the option of transplantation is usually not even presented to esented to families who have a child with sickle cell diseasefamilies who have a child with sickle cell disease

PanipintoPanipinto et al., (CIBMTR)et al., (CIBMTR)British J Haematol.British J Haematol.2007;137:4792007;137:479--485485

HSCT from unrelated donors

in patients with Thalassemia

Results of the GITMO study

Patient characteristicsPatient characteristicsNumber of patientsNumber of patients 5050

Sex (M / F)Sex (M / F) 28 / 2228 / 22 56% / 44%56% / 44%

Median age (years)Median age (years) 88 (1.5 (1.5 –– 17)17)

Pesaro classification:Pesaro classification:Class 1Class 1Class 2Class 2

23232727

46%46%54%54%

Iron chelation:Iron chelation:RegularRegularIrregularIrregular

444466

88%88%12%12%

Portal fibrosis:Portal fibrosis:NoNoMildMildModerateModerateUnknownUnknown

292915154422

58%58%30%30%8%8%4%4%

HCVHCV--RNA:RNA:NegativeNegativePositivePositive

444466

88%88%12%12%

ALT ALT –– AST > 2AST > 2--fold increase:fold increase:NoNoYesYes

454555

90%90%10%10%

DonorDonor--Recipient HLA compatibilityRecipient HLA compatibility

HLA Class I:HLA Class I:–– MatchedMatched 4242 (84%)(84%)–– MismatchedMismatched 88 (16%)(16%)

HLA Class IIHLA Class II::–– MatchedMatched 5050 (100%)(100%)

HLA DPB1HLA DPB1::–– MatchedMatched 1313 (26%)(26%)–– Mismatched Mismatched 3434 (68%)(68%)–– UnknownUnknown 33 (6%)(6%)

Acute GVHD garde III-IV

0 10 20 30 40 50 60 70 80 90 100

Days

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cum

ulat

ive

inci

denc

e

15% (8-30%)

Grade III-IV acute GVHD

Primary Graft Failure

0 10 20 30 40 50 60 70 80 90 100

Days

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cum

ulat

ive

inci

denc

e

8% (3-20%)

Chronic GVHD - extensive

0 1 2 3 4 5 6 7 8 9 10 11 12

Years

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Cum

ulat

ive

inci

denc

e

7% (0-15%)

Transplant-Related Mortality

0 1 2 3 4 5 6 7 8 9 10 11 12

Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cum

ulat

ive

inci

denc

e

6% (2-19%)

Overall Survival

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prob

abili

ty94% (87-100%)

Thlasse mia-Free Survival

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prob

abili

ty82% (71-94%)

Thalassemia-free survival

Thlasse mia-Free Survival

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prob

abili

ty88% (78-97%)

Thalassemia-free survival < 15 years

ConclusionsConclusions

HSCT from unrelated volunteers is able to cure a HSCT from unrelated volunteers is able to cure a proportion of patients with thalassemia comparable proportion of patients with thalassemia comparable to that cured with an allograft from a compatible to that cured with an allograft from a compatible sibling, provided that an accurate selection of the sibling, provided that an accurate selection of the donor is employed;donor is employed;

Results are mainly dependent on patientResults are mainly dependent on patient’’s clinical s clinical conditions and age;conditions and age;

It remains to be established who are the optimal It remains to be established who are the optimal candidates for this innovative procedure.candidates for this innovative procedure.

High Graft Failure Rates after High Graft Failure Rates after Unrelated Cord Blood Unrelated Cord Blood Transplantation for Transplantation for Thalassemia Major and Sickle Thalassemia Major and Sickle Cell Disease.Cell Disease.

Vanderson Rocha, Mary Eapen, Eliane Gluckman, Vanderson Rocha, Mary Eapen, Eliane Gluckman, WagnaraWagnara ChavesChaves, Mary , Mary M. Horowitz, Joanne Kurtzberg, John Wingard and John E. Wagner M. Horowitz, Joanne Kurtzberg, John Wingard and John E. Wagner

for the Eurocord Registry, Paris, France and the Center for Intefor the Eurocord Registry, Paris, France and the Center for International Blood rnational Blood and Marrow Transplant Research, Milwaukee, U.S.Aand Marrow Transplant Research, Milwaukee, U.S.A

First UCB transplantsFirst UCB transplants–– N=25 patientsN=25 patients–– 1998 to 2006 1998 to 2006 –– Centres=17 Centres=17 –– DiseasesDiseases

ThalThal major (N=16) major (N=16) SCD (N=9) SCD (N=9)

Median age at Median age at TxTx: 5 years (0.2: 5 years (0.2--15) 15)

Median followMedian follow--up: 29 months (4up: 29 months (4--98) 98)

PatientsPatients

THALTHALN=16N=16

SCDSCDN=9N=9

StrokeStroke -- 55

Acute Chest Acute Chest SyndromeSyndrome -- 44

Pesaro IPesaro I 8 8 --

Pesaro IIPesaro II 4 4 --

Time from Time from diagdiag to to UCBT (years)UCBT (years) 3.7 (0.13.7 (0.1--15)15) 5.14 (0.65.14 (0.6--8)8)

Disease CharacteristicsDisease CharacteristicsIndications for UCBTIndications for UCBT

Transplant CharacteristicsTransplant Characteristics

THALTHALN=16N=16

SCDSCDN=9N=9

*HLA Matched (6/6)*HLA Matched (6/6)11--locus MMlocus MM22--loci MMloci MM

336677

112266

Median number of NC Median number of NC infused/kg x10infused/kg x1077 5.3 (2.55.3 (2.5--39)39) 5.7 (2.95.7 (2.9--9.3)9.3)

*HLA definition : HLA-A and-B by low resolution typing and DRB1 by high resolution typing1 patient with Thal major received 2 UCB units

Transplant CharacteristicsTransplant Characteristics

THALTHALN=16N=16

SCDSCDN=9N=9

GVHD prophylaxisGVHD prophylaxisCsA aloneCsA aloneCsA+steroidCsA+steroidCsA+MMFCsA+MMFFK506 (FK506 (±±MMFMMF±±steroidsteroid))

11554466

--441133

Conditioning regimenConditioning regimenMyeloablativeMyeloablativeBU+CY+ATGBU+CY+ATGBU+otherBU+otherReduced IntensityReduced IntensityBU+TLI+FLU+ATGBU+TLI+FLU+ATGMelphalan+FLU+ATGMelphalan+FLU+ATGFLU+TBI 2GyFLU+TBI 2GyFlU+CY+TLIFlU+CY+TLI 2Gy+ATG2Gy+ATG

131377663 3 111111--

7755222211----11

Use of ATG/Use of ATG/CampathCampath 10/010/0 8/1 8/1

THALTHALN=16N=16

SCDSCDN=9N=9

ANC500 @d28ANC500 @d28 1212 55

Full chimerismFull chimerism 99 33

Second transplantsSecond transplants(after 1(after 1stst TxTx))

33(0.3; 9 &10 months)(0.3; 9 &10 months)

22(1 & 8 (1 & 8

months)months)

Grade 2Grade 2--4 acute GVHD @d1004 acute GVHD @d10066

grade II n=4grade II n=4grade III n=2grade III n=2

00

Chronic GVHD @2 yrsChronic GVHD @2 yrs 2 of 92 of 9 0 of 30 of 3

Hematopoietic Recovery Hematopoietic Recovery Graft versus Host DiseaseGraft versus Host Disease

THALTHALN=16N=16

SCDSCDN=9N=9

Causes of DeathCauses of DeathVODVODOrgan failureOrgan failureInfectionInfectionChronic GVHDChronic GVHD

6611222211

00

Event Free SurvivalEvent Free Survival 55 33

EFS by Conditioning regimenEFS by Conditioning regimen

MyeloablativeMyeloablativeReduced intensityReduced intensity

5/135/130/30/3

3/73/70/20/2

Mortality and Event free survivalMortality and Event free survival

ConclusionConclusion

Graft failure is a challenge in these Graft failure is a challenge in these patients patients

All 5 recipients of reduced intensity All 5 recipients of reduced intensity conditioning regimen had graft failure conditioning regimen had graft failure

Exploration of novel approaches in Exploration of novel approaches in prospective clinical trials is needed.prospective clinical trials is needed.

Sibling cord blood Sibling cord blood bankingbanking

Program LogisticsProgram LogisticsOakland sibling bank (B. Lubin)Oakland sibling bank (B. Lubin)

Family and physician contact staff and enroll following informedFamily and physician contact staff and enroll following informedconsent. Maternal and patient medical history obtained. consent. Maternal and patient medical history obtained. Maternal testing for infectious disease.Maternal testing for infectious disease.

Collection kit sent to familyCollection kit sent to family

CB collected at time of delivery by the obstetrician/midwife anCB collected at time of delivery by the obstetrician/midwife and d shipped to the lab for processingshipped to the lab for processing

Samples processed and cryopreserved within 48 hours of Samples processed and cryopreserved within 48 hours of collectioncollection

DiseasesN=107

Sibling Cord Blood Banking Sibling Cord Blood Banking Fraction of CBUs released for UCBTFraction of CBUs released for UCBT2531 total2531 total

Malignant diseasesMalignant diseases 3535

Sickle CellSickle Cell 2222

Other/RareOther/Rare 2424

ThalassemiaThalassemia 2626

SDCB Units Collected, HLA matched, SDCB Units Collected, HLA matched, Number Released for TransplantNumber Released for Transplant

June 2007

CategoriesCategories No. Collected (HLA No. Collected (HLA Matched)Matched) No. ReleasedNo. Released % Released % Released

(HLA Matched)(HLA Matched)

Malignant DiseasesMalignant Diseases 1,096 (250)1,096 (250) 3535 3% (14%)3% (14%)

Sickle CellSickle Cell 673 (170)673 (170) 2020 3% (11%)3% (11%)

ThalassemiaThalassemia 131 (33)131 (33) 2323 18% (70%)18% (70%)

OtherOther 329 (80)329 (80) 2424 7% (30%)7% (30%)

TotalTotal 2,229 (557)2,229 (557) 102102 5% (18)5% (18)

Why do these differences between thalassemia and SCD exist?Why do these differences between thalassemia and SCD exist?Criteria for transplantation differ (disease severity for SCA, Criteria for transplantation differ (disease severity for SCA,

transfusion and chelation for thalassemia)transfusion and chelation for thalassemia)Transplant considered to risky by parents or by treating Transplant considered to risky by parents or by treating

physicianphysicianSickle cell disease is clinically variable compared to Sickle cell disease is clinically variable compared to

thalassemia thalassemia Centers where patients are treated do not perform Centers where patients are treated do not perform

transplantationtransplantationParents are not explained risks/options for transplantation by Parents are not explained risks/options for transplantation by

treating physicians without biastreating physicians without bias

Decision making issues regarding CB transplantation for SCDDecision making issues regarding CB transplantation for SCD

Role of PhysicianRole of Physician-- Bias against transplantationBias against transplantation-- DonDon’’t perform transplantationt perform transplantation-- Risk/benefit considerationsRisk/benefit considerations

Psychosocial FactorsPsychosocial Factors-- Family not explained optionsFamily not explained options-- Considered to riskyConsidered to risky-- Child doing well at the timeChild doing well at the time-- Family empowerment? Family empowerment? CulturalCultural

EconomicsEconomics-- Economics of family and impact of transplantEconomics of family and impact of transplant-- InsuranceInsurance

Challenges to overcome for worldwide sibling CB Challenges to overcome for worldwide sibling CB banking for Hb disordersbanking for Hb disorders

Public Health IssuesPublic Health IssuesCollection staffCollection staffInformed consentInformed consentTransportation to laboratoryTransportation to laboratoryLaboratory proceduresLaboratory proceduresTransplantation facilitiesTransplantation facilitiesCostCost

haematopoietic stem cell transplantation in...

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