hematopoietic stem cell transplantation in pediatrics

Hematopoietic stem cell Hematopoietic stem cell transplantationtransplantation in in

PediatricsPediatrics

Hedayati Asl A.Hedayati Asl A.Ped. Hemato. & OncologistPed. Hemato. & Oncologist

BMTBMTMAHAK Children’s Cancer HospitalMAHAK Children’s Cancer Hospital

HSCT HSCT -- definitiondefinition

�� DefinitionDefinitionAAny procedure where hematopoietic stem ny procedure where hematopoietic stem cells of any donor and any source are given to cells of any donor and any source are given to cells of any donor and any source are given to cells of any donor and any source are given to a recipient with intention of a recipient with intention of repopulating/replacing the hematopoietic repopulating/replacing the hematopoietic system in total or in partsystem in total or in part

History

• Hematopoietic stem cell transplantation in the mouse

• the radiation protection phenomenon (mid-1950s)

• Hematopoietic stem cell tranplantation in the dog• Hematopoietic stem cell tranplantation in the dog

• Hematopoietic stem cell tranlsplantation in human

patients

• 1959–1963 : first allogeneic HSCT in humans

• beginning of the Modern Era of HSCT: the end of 1960

History of BM transplantationHistory of BM transplantation

�� 1956 1956 –– 11stst marrow infusionmarrow infusion

�� 1968 1968 –– 11stst successful BMTsuccessful BMT

1981 1981 –– 11stst thalassaemiathalassaemia TxTx�� 1981 1981 –– 11stst thalassaemiathalassaemia TxTx

�� 1988 1988 –– 11stst cord blood transplantcord blood transplant

The Nobel Prize, 1990

E. Donnall Thomas

first succsessful HSCT in treatment of acute leukemias

Thomas ED, Lochte HL, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N. Engl. J. Med. 1957; 257: 491.

Nobel PrizesNobel Prizes

�� 19801980:Jean Dausset, Baruj Benacerraf and :Jean Dausset, Baruj Benacerraf and George D. Snell for work on HLA systemGeorge D. Snell for work on HLA system

�� 19901990: Dr E Donall Thomas : Dr E Donall Thomas –– Seattle for Seattle for work in clinical marrow transplantationwork in clinical marrow transplantation

Stem cells

population of undifferentiated cells which are able

• to divide for indefinite period

• to self renew

• to generate a functional progeny of highly specialised cellscells

Plasticity and

transdifferentiate of

stem cells: potential stem cells: potential

clinical impact in

regenerative

medicine

SourceSource

Hematopoietic stem cells

1 / 25 000 - 100 000 of bone marrow cells

Charakteristic:

• CD34

• CD133

• Lin-

• C-kit (CD117)

• BCRP

Blood, 15 Jan 2004

PathologyPathology

�� Treat Leukemia by chemotherapyTreat Leukemia by chemotherapy

�� Regeneration of normal marrow Regeneration of normal marrow

�� Chemotherapy alone cannot eliminate all Chemotherapy alone cannot eliminate all �� Chemotherapy alone cannot eliminate all Chemotherapy alone cannot eliminate all malignant cells malignant cells

�� Stem cell transplants. Stem cell transplants.

TransplantTransplant

�� Patient's bone marrow stem cells are Patient's bone marrow stem cells are replaced with healthy cells replaced with healthy cells

�� Existing bone marrow and abnormal Existing bone marrow and abnormal �� Existing bone marrow and abnormal Existing bone marrow and abnormal leukocytes killedleukocytes killed

�� Chemotherapy and radiationChemotherapy and radiation

�� Next bone marrow containing healthy Next bone marrow containing healthy stem cells restem cells re--infused infused

�� Introduction/OverviewIntroduction/Overview

Specific DiseasesSpecific Diseases

Overview of Blood and Marrow Transplantation

History of BMTDefinitions

RationaleStem cell sources

�� Specific DiseasesSpecific Diseases

�� Alternative Stem Cell Alternative Stem Cell TransplantationTransplantation

�� Supportive MeasuresSupportive Measures

AML ALLBreast cancerNHL

MDSMultiple MyelomaHodgkin’s disease

IndicationsIndications

�� Hematological diseasesHematological diseases

Benign : Thallassaemia, Aplastic Benign : Thallassaemia, Aplastic Anaemia Anaemia Anaemia Anaemia

Malignant : Leukemia Lymphoma Malignant : Leukemia Lymphoma MyelomaMyeloma

�� Immune deficiency disorders Immune deficiency disorders

Pediatric and AdultPediatric and Adult

�� Neurological Disease (MS)Neurological Disease (MS)

Indication for HSCTIndication for HSCT

�� Neoplastic disordersNeoplastic disorders�� Hematological malignanciesHematological malignancies

�� Lymphomas (Hodgkin and nonLymphomas (Hodgkin and non--Hodgkin)Hodgkin)

�� Leukemias (acute and chronic)Leukemias (acute and chronic)

�� Multiple myelomaMultiple myeloma

�� MDSMDS�� MDSMDS

�� Solid tumorsSolid tumors

�� NonNon--neoplastic disordersneoplastic disorders�� Aplastic anemiaAplastic anemia

�� Autoimmune diseasesAutoimmune diseases

�� ImmunodeficiencyImmunodeficiency

�� Inborn errors of metabolismInborn errors of metabolism

Potential Stem Cell Sources

�� AutologousAutologous stem cellsstem cells

�� HLAHLA--matched related donorsmatched related donors

�� HLAHLA--matched unrelated matched unrelated donorsdonors

�� HaploidenticalHaploidentical related donorsrelated donors

�� Umbilical cord bloodUmbilical cord blood

Stem Cell Sources

�� Bone MarrowBone Marrow

�� BloodBlood�� BloodBlood

�� Umbilical CordUmbilical Cord

�� Fetal LiverFetal Liver

Sources of stem cellsSources of stem cells

�� Bone marrowBone marrow

�� Peripheral bloodPeripheral bloodPeripheral bloodPeripheral blood

�� Umbilical cord bloodUmbilical cord blood

�� Fetus liverFetus liver

HSCTHSCT

�� Allogeneic HSCTAllogeneic HSCT

�� syngeneicsyngeneic

�� from sibling/related donorfrom sibling/related donor�� from sibling/related donorfrom sibling/related donor

�� from unrelated donorfrom unrelated donor

�� Autologous HSCT Autologous HSCT

Types of stem cell for Types of stem cell for transplantationtransplantation

�� Autologous adultAutologous adult

�� Allogeneic adultAllogeneic adult

�� Foetal (cord blood)Foetal (cord blood)�� Foetal (cord blood)Foetal (cord blood)

�� EmbryonicEmbryonic

�� MesenchymalMesenchymal

TransplantationTransplantation

�� Autologous Autologous

�� Allogeneic Allogeneic �� Allogeneic Allogeneic

�� Syngeneic Syngeneic

types of stem cell transplants

� AUTOLOGOUS TRANSPLANTS - Patients

receive their own stem cells.

� SYNGENEIC TRANSPLANTS - Patients

receive stem cells from their identical twin.receive stem cells from their identical twin.

� ALLOGENEIC TRANSPLANTS - Patients

receive stem cells from someone other than

the patient or an identical twin.

ProcedureProcedure

�� Most blood stem cells reside in the bone Most blood stem cells reside in the bone marrow and a small number are present in marrow and a small number are present in the bloodstream the bloodstream the bloodstream the bloodstream

�� Multipotent peripheral blood stem cellsMultipotent peripheral blood stem cells

�� Can be obtained from drawn bloodCan be obtained from drawn blood

�� PBSCs are easier to collect than bone PBSCs are easier to collect than bone marrow stem cells marrow stem cells

ProcedureProcedure

�� Bone Marrow versus Peripheral Stem CellsBone Marrow versus Peripheral Stem Cells

�� AccessibilityAccessibility

�� CostCost�� CostCost

�� Sample sizeSample size

�� Donor/Patient factorsDonor/Patient factors

�� ExpertiseExpertise

GG--CSF mobilisationCSF mobilisationG-CSF only mobilisation

25

30

35

0

5

10

15

20

1 2 3 4 5 6

Day

Wh

ite

cell

s

WBC

G-CSF

Harvest

CyclophosphamideCyclophosphamide mobilisationmobilisationCyclo primed mobilisation

8

10

12

WBC

0

2

4

6

8

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Day

Wh

ite

cell

s WBC

G-CSF

Cyclo

Harvest

Bone marrow harvestingBone marrow harvesting

�� General anaestheticGeneral anaesthetic

�� Marrow aspirated from pelvis (+sternum)Marrow aspirated from pelvis (+sternum)

�� Marrow filtered to remove debrisMarrow filtered to remove debris�� Marrow filtered to remove debrisMarrow filtered to remove debris

�� Marrow may be administered “fresh” or Marrow may be administered “fresh” or cryocryo--preservedpreserved

Peripheral blood harvestingPeripheral blood harvesting�� Stem cells mobilised Stem cells mobilised ––

�� GG--CSF in healthy donorsCSF in healthy donors

�� Cyclophosphamide + Cyclophosphamide + GG--CSF in patientsCSF in patients

�� On day On day 5 5 (donors), day (donors), day 10 10 (patients)(patients)10 10 (patients)(patients)�� 3 3 hours session on stem hours session on stem

cell collection machinecell collection machine

�� Stem cells given fresh or Stem cells given fresh or cryopreservedcryopreserved

HarvestingHarvesting

Collection of hematopietic stem cells

bone marrow peripheral blood

Stem cell harvestingStem cell harvesting

�� Autologous and allogeneic, from Autologous and allogeneic, from peripheral blood or bone marrowperipheral blood or bone marrow

�� Foetal Foetal –– placental cord blood “milking”placental cord blood “milking”�� Foetal Foetal –– placental cord blood “milking”placental cord blood “milking”

�� EmbryonicEmbryonic

�� MesenchymalMesenchymal

Umbilical Cord Blood Stem Cell Umbilical Cord Blood Stem Cell TransplantTransplant

�� Umbilical cords have traditionally been Umbilical cords have traditionally been discarded as a bydiscarded as a by--product of the birth product of the birth process. process. process. process.

�� PluripotentPluripotent--stemstem--cellcell--rich blood found in rich blood found in the umbilical cord rich in marrow stem the umbilical cord rich in marrow stem cells and PBSC’s. cells and PBSC’s.

Umbilical Cord Umbilical Cord TxTx

�� Umbilical cord transplants are less prone Umbilical cord transplants are less prone to rejection. to rejection.

�� Cells have not yet developed the features Cells have not yet developed the features �� Cells have not yet developed the features Cells have not yet developed the features that can be recognized and attacked by that can be recognized and attacked by the recipient's immune system. the recipient's immune system.

�� Umbilical cord blood lacks wellUmbilical cord blood lacks well--developed developed immune cells, there is smaller incidence of immune cells, there is smaller incidence of graft versus host disease. graft versus host disease.

HematologyHematology-- Oncology and Oncology and Bone Marrow Bone Marrow

Transplantation Research Transplantation Research Center, Tehran University Center, Tehran University

of Medical Sciencesof Medical Sciences

Unrelated cord blood Unrelated cord blood transplantation in severe transplantation in severe

combined combined immunodeficiency immunodeficiency

patient, first report in patient, first report in IranIran

Hierarchy

• Totipotent (fertilised egg)

• Pluripotent (embryonic cell)

• Multipotent (hematopoietic)

Cord BloodCord Blood

Cord Blood Transplantation

Advantages Disadvantages

Waste product of normal deliveries

Readily available

One unit rescues one patient/no DLI

Theoretical risk of genetic disease transmission

Increased availability for minorities

Decreased transmission of viruses (e.g. CMV)

disease transmission

Theoretical risk of maternal cell contamination (GVHD)

Efficacy in adults unknown

CONDITIONING CONDITIONING (PREPARATIVE) REGIMEN(PREPARATIVE) REGIMEN

�� To suppress the patient’s To suppress the patient’s immune system from rejecting immune system from rejecting immune system from rejecting immune system from rejecting the stem cells.the stem cells.

�� To eliminate the cancerTo eliminate the cancer

Conditioning regimensConditioning regimens

�� PrinciplesPrinciples�� „space„space--making” making” (controversial)(controversial)

�� immunosuppressionimmunosuppression

�� disease eradicationdisease eradication�� disease eradicationdisease eradication

�� StrategyStrategy�� Ablative therapyAblative therapy

�� radio/chemoradio/chemo

�� Reduced intensity therapyReduced intensity therapy�� radio/chemoradio/chemo

�� NonNon--myloablative therapymyloablative therapy�� radio/chemoradio/chemo

Auto TransplantAuto Transplant

Criteria

�� Tumor with dose response curveTumor with dose response curve

�� Tumor sensitive to Tumor sensitive to myelosuppressivemyelosuppressive agentsagents

Autologous Bone Marrow Transplantation

Tumor sensitive to Tumor sensitive to myelosuppressivemyelosuppressive agentsagents

�� Purging techniques if marrow is contaminatedPurging techniques if marrow is contaminated�� with tumorwith tumor

-- Preserve stem cellsPreserve stem cells-- Eradicate tumorEradicate tumor

�� Technique for peripheral stem cell collectionsTechnique for peripheral stem cell collections

�� Minimal tumor burdenMinimal tumor burden

�� Marrow ablation Marrow ablation

Purpose of Purpose of AutologousAutologousTransplantationTransplantation

�� To allow administration of high dose To allow administration of high dose (supra(supra--lethal) therapylethal) therapy

�� Use when patient has achieved best Use when patient has achieved best �� Use when patient has achieved best Use when patient has achieved best response to initial chemotherapyresponse to initial chemotherapy

�� Autologous stem cells “rescue” patient Autologous stem cells “rescue” patient from high dose therapyfrom high dose therapy

�� No immunological conflictNo immunological conflict

Disadvantages of Disadvantages of AutologousAutologoustransplanttransplant

�� Stem cell donation may be contaminated Stem cell donation may be contaminated by tumour cellsby tumour cells

�� Pre transplant purging may be used, inPre transplant purging may be used, in--vivo vivo �� Pre transplant purging may be used, inPre transplant purging may be used, in--vivo vivo or inor in--vitrovitro

�� No graft versus tumour effectNo graft versus tumour effect

Benefits of Benefits of AutologousAutologousTransplantTransplant

�� May provide sufficient antiMay provide sufficient anti--tumour effect tumour effect to leave very few tumour cellsto leave very few tumour cells

�� Residue becomes nonResidue becomes non--viable (possibly due to viable (possibly due to �� Residue becomes nonResidue becomes non--viable (possibly due to viable (possibly due to recovery of NK cell activity)recovery of NK cell activity)

�� Cure can be achievedCure can be achieved

�� Low transplant related mortality (TRM) Low transplant related mortality (TRM) ––33%%

Patient “pathway” in Patient “pathway” in autograftautograft

�� 28 28 day inday in--patient staypatient stay�� Some daySome day--case, home therapy casescase, home therapy cases

�� Nausea/vomitingNausea/vomiting�� MucositisMucositis�� MucositisMucositis�� Marrow failureMarrow failure�� Infections, bleeding tendencyInfections, bleeding tendency�� “Graft” may occur as early as day “Graft” may occur as early as day 99--1010�� Rising neutrophils and plateletsRising neutrophils and platelets�� Discharge home and recovery phase (Discharge home and recovery phase (33--12 12 months)months)

Haematological chart in Haematological chart in autograftautograftAutologous PBSCT

7

8

9

10

300

350

400

450stem cells

0

1

2

3

4

5

6

-5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Days

Neu

ts

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100

150

200

250

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Plt

s

Neuts

Plts

Chemo

PBSC

Application of Application of AutologousAutologoustransplanttransplant

�� Myeloma Myeloma –– in in 11stst remissionremission

�� Lymphomas Lymphomas –– in in 22ndnd remissionremission

�� AML AML –– has greater antihas greater anti--leukaemicleukaemic effect, but effect, but high riskhigh riskhigh riskhigh risk

�� ALL ALL –– no benefitno benefit

�� Solid tumoursSolid tumours�� No benefit in breast cancerNo benefit in breast cancer

�� Occasional use in less common tumoursOccasional use in less common tumours

�� Autoimmune disorders inc. ITPAutoimmune disorders inc. ITP

�� Neurological disorders inc. MSNeurological disorders inc. MS

Complications of Complications of AutograftingAutografting

�� Procedure related mortalityProcedure related mortality

�� Poor quality of lifePoor quality of life

�� Early relapse may be more aggressive Early relapse may be more aggressive �� Early relapse may be more aggressive Early relapse may be more aggressive

�� 22ndnd CancersCancers

AllotransplantAllotransplant

AllogeneicAllogeneic transplantationtransplantation

�� Donors:Donors:

�� Syngeneic twinSyngeneic twin

�� Matched sibling donorMatched sibling donor�� Matched sibling donorMatched sibling donor

�� MisMis--matched family donormatched family donor

�� Matched unrelated donorMatched unrelated donor

�� Cord blood donationCord blood donation

�� “Saviour” sibling“Saviour” sibling

�� “Matched” unrelated cord“Matched” unrelated cord--bloodblood

Haplo-identical HSCT

Advantages Disadvantages

Nearly all patients have a donor

Share major (e.g. HLA-C)

HLA Barriers:-Graft rejection-GVHDShare major (e.g. HLA-C)

and minor hitocompatibility antigens

Immediate donor availability

-GVHD-Immunedysregulation

Recovering from the transplantRecovering from the transplant

�� Recovery of normal levels cells is called engraftmentRecovery of normal levels cells is called engraftment

�� Day Day 8 8 -- 12 12

�� Neutrophil engraftment important (GCSF) may be Neutrophil engraftment important (GCSF) may be given to accelerate the processgiven to accelerate the processgiven to accelerate the processgiven to accelerate the process

�� Platelets are the next to return with red cells last.Platelets are the next to return with red cells last.

�� Commonly patients require transfusion of red cells Commonly patients require transfusion of red cells and platelets following a transplant.and platelets following a transplant.

�� Discharge upon neutrophil & platelet engraftmentDischarge upon neutrophil & platelet engraftment

Stem Cell TransplantStem Cell Transplant

Complications of BM donationComplications of BM donation

�� Bone marrow donorsBone marrow donors�� Post operative painPost operative pain�� AnaemiaAnaemia

�� Minnesota dataMinnesota data�� Minnesota dataMinnesota data�� 493 493 donors: age range donors: age range 19 19 –– 5656�� Marrow volume: mean Marrow volume: mean 10501050ml (ml (180180--29832983ml)ml)�� Autologous blood transfusion Autologous blood transfusion 9898..88%%�� Allogeneic blood Allogeneic blood 00..66%%�� 1 1 donor apnoeic under anaesthesiadonor apnoeic under anaesthesia�� 7474..88% pain at collection sites% pain at collection sites�� Mean duration to full recovery Mean duration to full recovery 15 15 days (days (1010% >% >30 30 days)days)

Peripheral blood stem cell donorsPeripheral blood stem cell donors

�� Access site bruising/painAccess site bruising/pain

�� GG--CSF induced bone pain CSF induced bone pain –– 8080%%�� Allergy to gAllergy to g--csf (csf (1 1 in in 300300))

�� ARDS and alveolar haemorrhageARDS and alveolar haemorrhage

�� Patients may experience neutropenic infectionPatients may experience neutropenic infection

�� Excessive white cell drive Excessive white cell drive –– has been linked to splenic has been linked to splenic rupture (?rupture (?1 1 in in 40004000))

�� Apheresis reactionsApheresis reactions

�� Cardiovascular events due to plaque inflammationCardiovascular events due to plaque inflammation

�� Deep vein thrombosis/pulmonary embolismDeep vein thrombosis/pulmonary embolism

�� No evidence of increased haematological malignancyNo evidence of increased haematological malignancy

Peripheral blood stem cell donorsPeripheral blood stem cell donors

�� Access site bruising/painAccess site bruising/pain

�� GG--CSF induced bone pain CSF induced bone pain –– 8080%%�� Allergy to gAllergy to g--csf (csf (1 1 in in 300300))

�� ARDS and alveolar haemorrhageARDS and alveolar haemorrhage

�� Patients may experience neutropenic infectionPatients may experience neutropenic infection

�� Excessive white cell drive Excessive white cell drive –– has been linked to splenic has been linked to splenic rupture (?rupture (?1 1 in in 40004000))

�� Apheresis reactionsApheresis reactions

�� Cardiovascular events due to plaque inflammationCardiovascular events due to plaque inflammation

�� Deep vein thrombosis/pulmonary embolismDeep vein thrombosis/pulmonary embolism

�� No evidence of increased haematological malignancyNo evidence of increased haematological malignancy

Stem cell processing and storageStem cell processing and storage

�� Donation divided into Donation divided into 6060ml aliquotsml aliquots

�� Cells cooled to Cells cooled to 00ooC on iceC on ice

�� 1010% DMSO added% DMSO added�� 1010% DMSO added% DMSO added

�� Cells frozen to Cells frozen to --4040ooC at rate of C at rate of --1010oo/min/min

�� Frozen bags moved into gaseous phase Frozen bags moved into gaseous phase liquid nitrogenliquid nitrogen

�� Bags stored in liquid phase nitrogen Bags stored in liquid phase nitrogen at approximately at approximately --200200ooCC

Stem cell thawing and Stem cell thawing and administrationadministration

�� Bags warmed in Bags warmed in 3737ooC waterbathC waterbath

�� DMSO is toxic to stem cells at >DMSO is toxic to stem cells at >00ooCC

�� Administer cells as an infusion over <Administer cells as an infusion over <10 10 �� Administer cells as an infusion over <Administer cells as an infusion over <10 10 mins via a central venous linemins via a central venous line

�� PrePre--treat patient with paracetamol and treat patient with paracetamol and antianti--emeticsemetics

Bone marrow transplantation unit

Hematopoietic stem cell infusion

EBMT Database

Acute leukaemias: AML 25488 27532

Acute leukaemias: ALL 17328 18521

Acute leukaemias: other/unknown 907 1004

Chronic leukaemias: CML 15344 16526

Chronic leukaemias: CLL 1835 1942

Chronic leukaemias: other/unknown 383 433

Lymphomas: NHL 30399 33109

Lymphomas: Hodgkins 10883 11865

Lymphomas: other/unknown 1592 1863

Disease Patients Procedures

Lymphomas: other/unknown 1592 1863

Mutiple myeloma/Plasma cell disorders 23152 30204

Solid tumours 22973 29430

Myelodysplastic/myeloproliferative 4868 5381

Aplastic anaemias 4478 5012

Immune deficiencies 1687 1938

Other inborn errors 724 818

Autoimmune diseases 405 417

Haemoglobinopathies 2223 2314

Other/unknown 322 394

Total 164991 188703

Note: Data reporting is incomplete, in particular for the most recent years

Number of procedures

100001200014000160001800020000

EBMT Database Number of procedures by year

02000400060008000

10000

<19

78

1979

1981

1983

1985

1987

1989

1991

1993

1995

1997

1999

2001

2003

Note: Data reporting is incomplete, in particular for the most recent years

8000

10000

12000

14000AlloAuto

EBMT Database Number of Procedures by Type of Transplant

6000700080009000

1000011000120001300014000

Allo

Auto

0

2000

4000

6000

1968

1972

1975

1978

1981

1984

1987

1990

1993

1996

1999

2002

0100020003000400050006000

<197

8

1979

1981

1983

1985

1987

1989

1991

1993

1995

1997

1999

2001

2003

Auto

Note: Data reporting is incomplete, in particular for the most recent years

THE FUNCTION OF BMT THE FUNCTION OF BMT UNIT UNIT

Handling services & Intensive care for: Handling services & Intensive care for:

�� Mobilization / stem cell collection & Mobilization / stem cell collection & �� Mobilization / stem cell collection & Mobilization / stem cell collection & infusion. infusion.

�� Chemotherapy for pre Chemotherapy for pre -- transplant transplant

�� Pre & post care for Transplant patients. Pre & post care for Transplant patients.

TransplantationTransplantation

�� Unit is importantUnit is important

�� ExpertiseExpertise

�� FacilityFacility�� FacilityFacility

�� IsolationIsolation

�� ApheresisApheresis

�� Platelet and blood supportPlatelet and blood support

�� Motivated patientMotivated patient

Differences in treating adults and cDifferences in treating adults and childrenhildren

�� Underlying diseaseUnderlying disease�� DonorsDonors�� Family membersFamily members�� Information, educationInformation, education�� Early complicationsEarly complications

�� E.g. organ toxicities, E.g. organ toxicities, �� E.g. organ toxicities, E.g. organ toxicities, viral infectionsviral infections

�� Late complicationsLate complications�� Growth impairment, Growth impairment, dental damage, dental damage, social integrationsocial integration

�� Late effectsLate effects�� Fertility, Secondary Fertility, Secondary maliganciesmaligancies

Sibling donor,5 hours after bone marrow harvest

Prerequisits for a clinical Prerequisits for a clinical programprogram

�� Collection facilitiesCollection facilities

�� Stem cell processing facilitiesStem cell processing facilities

�� Transfusion Service: Transfusion Service: 24 24 hour availability of CMV appropriate and hour availability of CMV appropriate and irradiated blood productsirradiated blood products

Hygiene CoordinatorHygiene Coordinator�� Hygiene CoordinatorHygiene Coordinator

�� Technical SupportTechnical Support

�� Pharmacy: Pharmacy: 24 24 hour availability of medicationshour availability of medications

�� Radiotherapy experienced in TBI + childrenRadiotherapy experienced in TBI + children

�� EFI accredited HLA testing labEFI accredited HLA testing lab

�� Diagnostic labs Diagnostic labs forfor

�� Infection surveillance (esp. Viral)Infection surveillance (esp. Viral)

�� Chimerism testingChimerism testing

�� Immunologic reconstitution Immunologic reconstitution

Room reRoom requirementsquirements

�� Single rooms + Air Single rooms + Air filtration +Personal filtration +Personal shower/toiletshower/toilet

�� Acute + readmission Acute + readmission phasephase

�� Enough space for Enough space for equipmentequipment

�� Easy access to ICUEasy access to ICU

�� Separate working room Separate working room for stafffor staff

�� Conference RoomConference Room

�� Staff roomStaff room

�� Recreation zone for Recreation zone for parents/visitorsparents/visitors

Outpatient facilitiesOutpatient facilities

�� Possibility for patient Possibility for patient isolationisolation

�� Protection from Protection from transmission of infectious transmission of infectious agentsagents

Possibility for Possibility for �� Possibility for Possibility for administration ofadministration of�� Intravenous fluidsIntravenous fluids

�� MedicationsMedications

�� Blood ProductsBlood Products

Watch out!Watch out!

�� Construction periodsConstruction periods

�� WaterWater

�� Lack of flexibility (e.g. Lack of flexibility (e.g. different patient age, different patient age, gender, culture)gender, culture)gender, culture)gender, culture)

�� Appropriate rooms for Appropriate rooms for administration, administration, documentation, recordsdocumentation, records

�� space for further space for further developmentdevelopment

Minimum Staff Minimum Staff requirementrequirement

�� Sufficient nursing staffSufficient nursing staff�� Doctors: Program Director, Senior physicians, mid level practitioners Doctors: Program Director, Senior physicians, mid level practitioners

(!!!! Separate staff for outpatient care!!!!)(!!!! Separate staff for outpatient care!!!!)

�� Cognitive Skills:Cognitive Skills:�� Patient/Donor Selection, Indication for HSCTPatient/Donor Selection, Indication for HSCT�� High dose therapyHigh dose therapy�� TransfusionTransfusion�� Diagnosis and management of early and late organ toxicitiesDiagnosis and management of early and late organ toxicities�� Diagnosis and management of early and late organ toxicitiesDiagnosis and management of early and late organ toxicities�� Pain managementPain management�� Terminal CareTerminal Care�� Diagnosis and management of bacterial, viral and fungal infections in Diagnosis and management of bacterial, viral and fungal infections in

immunocompromized patientsimmunocompromized patients�� Diagnosis and management of actue and chronic GVHDDiagnosis and management of actue and chronic GVHD�� ImmunologyImmunology�� ChimerismChimerism�� Management of Graft failureManagement of Graft failure

�� Procedual Skills:Procedual Skills:�� Stem cell harvest from pediatric donors (bone marrow, PBSC)Stem cell harvest from pediatric donors (bone marrow, PBSC)�� Stem cell infusion Stem cell infusion �� Knowledge in stem cell processiong and cryopreservationKnowledge in stem cell processiong and cryopreservation

Permanent personnel:

Programme director (Pediatric Hemato-Oncology/HSCT)3 senior physicians (ped hem/onc) experienced in HSCT1-2 physicians (ped hem/onc) in higher specialist training for HSCT26 nurses (all pediatric diploma-nurses)

Children´s Hospital: STAFF requirement

26 nurses (all pediatric diploma-nurses)1 secretary nurse1 data manager1 pediatric psychologist2 kindergarten teachers1 pediatric physical therapist1 art therapist1 music therapist1 teacher

Additional staff to maintain Additional staff to maintain supportsupport--servicesservices

�� Dietary staffDietary staff�� PsychotherapistPsychotherapist�� Social workerSocial worker�� Physical TherapyPhysical Therapy�� Data ManagerData Manager

Transplant Transplant �� Transplant Transplant CoordinatorCoordinator

�� Teachers, Teachers, kindergarten kindergarten teachersteachers

�� Art therapist, music Art therapist, music therapisttherapist

�� TranslatorsTranslators�� Home care nurseHome care nurse

Tissue typingTissue typing

�� HLA HLA –– Human Leucocyte AntigenHuman Leucocyte Antigen

�� CoCo--dominant expression of maternal and dominant expression of maternal and paternal epitopes on all leucocytespaternal epitopes on all leucocytespaternal epitopes on all leucocytespaternal epitopes on all leucocytes

�� HLA: class HLA: class 1 1 ABC, class ABC, class 2 2 DR(Q,P,T) class DR(Q,P,T) class 3 3 othersothers

�� Blood group can be differentBlood group can be different

�� Sex does not have to be matchedSex does not have to be matched

HLAHLA

HLA complexHLA complex

HLA AllelesHLA Alleles

�� A: A: 767767

�� B: B: 11781178

�� C: C: 439439�� C: C: 439439

�� DR: DR: 3 3 alpha, alpha, 618 618 betabeta

�� DQ: DQ: 34 34 alpha, alpha, 96 96 betabeta

�� DP: DP: 27 27 alpha, alpha, 133 133 betabeta

�� January January 20092009

Family HLA InheritanceFamily HLA Inheritance

Factors influencing the outcome of HSCTFactors influencing the outcome of HSCT

�� Disease factorsDisease factors�� stagestage

�� Patient Patient -- related factorsrelated factors�� AgeAge

�� Donor Donor -- related factorsrelated factors�� Histopompatibility (HLA)Histopompatibility (HLA)�� Histopompatibility (HLA)Histopompatibility (HLA)

�� SexSex

�� Viral status (CMV positivity)Viral status (CMV positivity)

�� PeriPeri--transplant factorstransplant factors�� ConditioningConditioning

�� GVHD preventionGVHD prevention

�� Stem cell source and contentStem cell source and content

�� PostPost--transplant factorstransplant factors�� GVHDGVHD

ComplicationComplication

�� AllogeneicAllogeneic

�� EarlyEarly

�� infectioninfection

�� aGVHDaGVHD

�� bleedingbleeding

toxicitytoxicity

�� AutologousAutologous

�� EarlyEarly

�� infectioninfection

�� bleedingbleeding

�� toxicitytoxicity�� toxicitytoxicity

�� graft failuregraft failure

�� LateLate

�� chGVHDchGVHD

�� infectioninfection

�� relapserelapse

�� gonadal failuregonadal failure

�� secondary malignancysecondary malignancy

�� toxicitytoxicity

� Late

�� relapserelapse

�� infectioninfection

�� gonadal failuregonadal failure

�� secondary malignacysecondary malignacy

�� toxicitytoxicity

Graft versus host diseaseGraft versus host disease

�� Counterpart of Counterpart of graft versus graft versus tumour effecttumour effect

�� Acute <Acute <100 100 daysdays�� Acute <Acute <100 100 daysdays

�� May be lethalMay be lethal

�� Chronic >Chronic >100 100 daysdays

�� May be disablingMay be disabling

Graft versus host disease (GVHD)

AlloHSCT AlloHSCT -- graft versus host diseasegraft versus host disease

�� GVHD GVHD �� Acute (Acute (11-- 44°°) ) �� Chronic (limited, extensive)Chronic (limited, extensive)

�� ProphylaxisProphylaxisCyclospirineCyclospirine�� CyclospirineCyclospirine

�� MetotrexateMetotrexate

�� TreatmentTreatment�� CyclosporineCyclosporine

�� SteroidSteroid

�� Mycofenolate mofetilMycofenolate mofetil

�� Antithymocytic globulineAntithymocytic globuline

�� AntiAnti--TNF alfa, antiTNF alfa, anti--Il Il 22

Graft Verses Host Disease (GVHD)Graft Verses Host Disease (GVHD)

�� GVHD sometimes occurs with GVHD sometimes occurs with allogeneicallogeneic transplantation. transplantation. �� Lymphocytes from the donor graft attack the cells of the Lymphocytes from the donor graft attack the cells of the

hosthost�� GVHD can usually be treated with steroids or other GVHD can usually be treated with steroids or other

immunosuppressive agents. immunosuppressive agents. immunosuppressive agents. immunosuppressive agents. �� Acute GVHD occurs before day Acute GVHD occurs before day 100 100 postpost--transplant transplant �� Chronic GVHD occurs beyond day Chronic GVHD occurs beyond day 100 100 �� Recent advances have reduced the incidence and Recent advances have reduced the incidence and

severity of this postseverity of this post--transplant complication, but GVHD, transplant complication, but GVHD, directly or indirectly, still accounts for approximately directly or indirectly, still accounts for approximately 1515% of deaths in stem cell transplant patients% of deaths in stem cell transplant patients

�� Chronic GVHD can develop months or even years postChronic GVHD can develop months or even years post--transplanttransplant

GVHDGVHD

�� Skin/HairSkin/HairRash, scleroderma, Rash, scleroderma, lichenoidlichenoid skin changes, skin changes, dyspigmentation,alopeciadyspigmentation,alopecia

�� Eyes Eyes Dryness, abnormal Dryness, abnormal Schirmer'sSchirmer's Test, Test, cornealerosionscornealerosions, , conjunctivitisconjunctivitisconjunctivitisconjunctivitis

�� Mouth Atrophic changes, Mouth Atrophic changes, lichenoidlichenoid changes, changes, mucositis,ulcersmucositis,ulcers, , xerostomiaxerostomia, dental caries, dental caries

�� Lungs Lungs BronchiolitisBronchiolitis obliteransobliterans

�� GI tract GI tract Esophageal involvement, chronic nausea/vomiting, Esophageal involvement, chronic nausea/vomiting,

chronic diarrhea, chronic diarrhea, malabsorptionmalabsorption, fibrosis, , fibrosis, abdominaabdomina l l pain/crampspain/cramps

GVHDGVHD

�� LiverLiverAbnormal LFTs, biopsy abnormalities Abnormal LFTs, biopsy abnormalities

�� Genitourinary Genitourinary VaginitisVaginitis, strictures, , strictures, stenosisstenosis, cystitis, cystitisVaginitisVaginitis, strictures, , strictures, stenosisstenosis, cystitis, cystitis

�� Musculoskeletal Musculoskeletal Arthritis, contractures, Arthritis, contractures, myositismyositis, myasthenia, , myasthenia,

fascitiesfascities�� Hematologic Hematologic

Thrombocytopenia, Thrombocytopenia, eosinophiliaeosinophilia, , autoantibodiesautoantibodies

HSCT in children needs pediatric multidisciplinary HSCT in children needs pediatric multidisciplinary teamwork:teamwork:

�� Intensive Care including Intensive Care including apheresisapheresis

�� ImmunologyImmunology

�� SurgerySurgery

�� Pulmonary MedicinePulmonary Medicine

�� GastroenterologyGastroenterology�� GastroenterologyGastroenterology

�� NephrologyNephrology

�� CardiologyCardiology

�� PsychiatryPsychiatry

�� Radiation OncologyRadiation Oncology

�� InfectionInfection

�� EndocrinologyEndocrinology

�� Parents & siblingsParents & siblings