Introduc)on to Clinical Hematopoie)c Cell Transplantaon (HCT)

Introduc)ontoClinicalHematopoie)cCell

Transplanta)on(HCT)

GeorgeChen,MDFriday,May12,17

GoalsforToday

• WhatisHCT?• HowisHCTdoneandhowisittailoredtofitthepa)ent’sdiseaseandcircumstances?

• WhataresomeoftheclinicalproblemsinHCT?

ImportantConcepts

•  AutologousvsallogeneicHCT•  Myeloabla)vevsreducedintensitycondi3oningregimens

•  Autologous,syngeneic,matchedrelated,matchedunrelated,mismatchedandhaploiden)caldonors

•  Acutevs.chronicgra5versushostdisease•  Donorchimerism

WhatisHCT?

•  Bonemarrowtransplant•  Hematopoie)cstemcelltransplant

•  Hematopoie)cprogenitorcelltransplant

•  Peripheralbloodstemcelltransplant

Thetransferofhematopoie)cprogenitorandstemcellsfortherapeu)cpurposes

ImportantConcepts

•  AutologousvsallogeneicHCT•  Myeloabla)vevsreducedintensitycondi)oningregimens


•  Acutevs.chronicgraNversushostdisease•  Donorchimerism

BasicDefini)ons• AutologousHCT–Atransplantusingapa)ent’sowncellsforthegraN.

• AllogeneicHCT–Atransplantusinganotherperson’scellsforthegraN.

Pa)ent AutologousHCT

HighdoseChemo±XRT

RegularChemo±XRT

Freezer

8-14days

Cytotoxicity

ChemotherapydoseCytotoxicityChemotherapydose

Indica)onsforautoHCT

• Diseasesinwhichcytoreduc)on(bychemotherapy)iseffec)veanddosedependent– Germcelltumors(tes)cular)– Largecelllymphoma– Mantlecelllymphoma(usually)– Myeloma

• Replacementofhematopoiesis(rescuetherapy)

Pa)ent

AllogeneicHCT

RegularChemo±XRT

HighdoseChemo±

XRT

14-21days

Time

Donor

Indica)onsforalloHCT• Replacementofhematopoiesis– Aplas)canemia

• Immunemediatedeffectagainsttheunderlyingmalignancy

• Preven)onofrelapse– Acuteandchronicleukemia– Myelodysplas)csyndrome– Indolentlymphomas

Somethingtothinkabout

• Whattumorcharacteris3csareamenabletoautologousversusallogeneictransplanta3on?

•  Forlater:Whattumorcharacteris3cslendthemselvestomyeloabla3veversusreducedintensitycondi3oning?

AcuteGvHD(15%)

Infec)on(10%)

Other(5%)

ChronicGvHD,dead(15%)

Diseaserelapse(20%)

ChronicGvHD,alive(15%)

Aliveandwell(20%)

AllogeneicBMTSurvivalOutcomes(AML)

Atransplantisabetagainstthefuture

HighdoseChemo±

XRT

LeukemiaTherapy

95%

5%

65%

35%

Gene)cSubgroupAnalysis:RFS

time (months)

Rel

apse

-free

Sur

viva

l (%

)

0 12 24 36 48 60 72 84 96

0

20

40

60

80

100

NPM1+/FLT3 ITD-

time (months)

Rel

apse

-free

Sur

viva

l (%

)

0 12 24 36 48 60 72 84 96

0

20

40

60

80

100

p=0.71

donor n=35

no donor n=92 donor n=45

no donor n=125

p=0.02

Others

CourtesyofSchlenkRetal,NEJM2008

MUD Transplantation in Relapsed Patients with Unfavorable Genotype

other strategy n=67

MUD n=37

p<0.0001

time (months)

Surv

ival

afte

r rel

apse

(%)

0 12 24 36 48 60

0

20

40

60

80

100

Prognos3ccategoriesforAML•  Good

–  t(8:21),t(9:22),inv16,t(15:17)–  NPM1–  CEPB

•  Medium–  Normalkaryotype

•  Poor–  Mul3plekaryotypicabnormali3es–  Flt3ITDorTDK

•  Clinicalfactorsindica3ngapoorprognosis–  Induc3onfailure–  Priorhematologicdisorder

ImportantConcepts

•  AutologousvsallogeneicHCT•  Myeloabla)vevsreducedintensitycondi)oningregimens



Pa)ent

AllogeneicBMT

RegularChemo±XRT

HighdoseChemo±

XRT

14-21days

Time

Donor

ImmunologicEffectsofAllogeneicGraNs

•  GraN-versus-TumorEffects–Reac)onofthedonorimmunesystemagainsttherecipient’smalignancy

•  GraN-versus-HostEffects–Reac)onofthedonorimmunesystemagainsttherecipient’sbody)ssues.

•  Differentsidesofthesamecoin.

ProbabilityofRelapseA5er2,254HLA-iden3calSiblingTransplantsfor

EarlyLeukemia

Mln06_1.ppt

0 2 4 61 3 50

20

40

60

80

100

Prob

abilityofR

elap

se,%

Years

TCellDeple3on(n=401)

Twins(N=70)

NoGVHD(n=433)

AGVHDOnly(n=738)

AGVHD+CGVHD(N=485)CGVHDOnly(N=127)

IncreasingGVT

IncreasingGVH

CellKilling

Chemotherapydose Chemotherapydose

CellKilling

Pa3e

ntToxicity

Chemotherapydose

CellKilling

Chemotherapydose Chemotherapydose

CellKilling

Pa3e

ntToxicity

Chemotherapydose

Pa3e

ntToxicity

Chemotherapydose

Pa)ent

ReducedIntensityAlloBMT

RegularTherapy

±Chemo±XRT

14-21days

Time

Donor

Immunosuppression

Pa)ent

AllogeneicBMT

RegularChemo±XRT

HighdoseChemo±

XRT

14-21days

Time

Donor

Transplantregimens

Myelosuppression

Flu-CyFlu-Cy-ATGFlu-lowdoseTBIFluATGTLI/ATGFLU/CY/TBI200cGy

Cy-TBI1200cGYBu-CyMel200

Flu-MelFlu-BuFlu-Mel-TBI400cGy

RegimenRelatedToxicity

LaterGra5-versusDiseaseEffect EarlierAn3-DiseaseEffect

AlloNon-myeloabla3ve

AlloReducedIntensity

AutoandAlloMyeloabla3ve

Relapse

Reducedintensity

Myeloabla)on

MonthsChemo

Chemo Months

Bu, Mel, full dose TBI

Fludarabine Bu, Mel, full dose TBI

Cyclophosphamide

Fludarabine Bu, Mel, full dose TBI

Cyclophosphamide

4-hydroxy-cyclophosphamide

CytochromeP450

Aldophosphamide

Phosphoramidemustard(ac3ve)

Acrolein(ac3ve)

Aldehydedehydrogenase Carboxy

phosphamide(inac3ve)

Tautomer-iza3on

Cyclophosphamide


CytochromeP450

Aldophosphamide


Acrolein(ac3ve)



Tautomer-iza3on

ElevatedinstemcellsHigherinresAnglymphocytesversusacAvatedlymphocytes

Bornhauser,eta

l.LancetOncologyOct2012

1stCRMRD9/10MUD

Bornhauser,eta

l.LancetOncologyOct2012

Allpa3ents

41-60y/o

18-40y/o


• Whattumorcharacteris3csareamenabletomyeloabla3veversusreducedintensitycondi3oningallogeneictransplanta3on?

ImportantConcepts•  AutologousvsallogeneicHCT• Myeloabla)vevsreducedintensitycondi)oningregimens



Donorsourcereflectspurpose

Rescuehematopoiesis

Immunetherapy

Autologous XXX ?Allogeneic XXX XXX

Adjusted probabilities of leukemia-free survival rates after identical twin bone marrow transplantations with high

(more than 3 × 108 cells/kg) versus low (less than or equal to 3 × 108 cells/kg) cell doses.

Barrett A J et al. Blood 2000;95:3323-3327

©2000 by American Society of Hematology

HumanLeukocyteAn3gen(HLA)•  Proteinswhichpresentan3genicpep3destoTcells

•  Onsurfaceofmostbodycells•  Themostimportantproteinsintransplant•  Responsibleforgra5rejec3onandGvHD

HLA

•  ClassI–A,B,C•  ClassII–DR,DQ,DP

HLAInheritance

Chanceofamatchedsibling=1–0.75#ofsiblings

A2B7

DR01

A23B51DR04

A11B15DR11

A30B35DR13

A2B7

DR01

A11B15DR11

A23B51DR04

A11B15DR11

A2B7

DR01

A30B35DR13

A23B51DR04

A30B35DR13

HLA

•  (>1*1012haplotypes)2=>1*1024combina3ons

•  Frequenciesarenotequaldistributed•  Notallalleleshavebeeniden3fied

HLA DRB1 A B C DQB1Alleles 400 370 660 190 62

HLAExpressionLevel

•  Highexpressionlevel(HEL)an3gens–DRB1,A,B,C

•  Lowexpressionlevel(LEL)an3gens–DQ,DP,DRB3-5

Rela3veMismatchBetweenDonorSourcesParent1 Parent2

Donor DRB1

B A C DQ DP DRB1

B A C DQ DP

Related = = = = = =Unrelated = = = = = = = = = = = =LEL-MM = = = = ≠ = = = = = ≠ ≠HEL-MM ≠ = = = = = = = = = = =Haplo = = = ≠ ≠ ≠

Pidala,etal.Blood2015

DonorSelec)on

•  Humanleukocytean)gen(HLA)matching•  Relatedness•  Cytomegalovirusstatus•  Age•  Gender(parity)•  NotbloodABOtype(sofar)




BMT

BillinghamCriteria(1966)•  ThegraNmustcontainimmunologicallycompetentcells

•  Thehostmustpossessimportanttransplanta)onalloan)gensthatarelackinginthedonorgraN,sothatthehostappearsforeigntothegraN,andis,therefore,capableofs)mula)ngitan)genically

•  Thehostitselfmustbeincapableofmoun)nganeffec)veimmunologicalreac)onagainstthegraN,atleastforsufficient)meforthelamertomanifestitsimmunologicalcapabili)es;thatis,it(thegraN)musthavethesecurityoftenure

AcuteGvHD

•  Reac)onofdonor’simmunesystemagainsttherecipient’sbody)ssues

•  Manifestsasdiarrhea,skinrash,livertestabnormali)esusuallywithinthefirst100days.

•  ~20-50%ofallogeneictransplantswilldevelopsomeaGvHD

•  Associatedwitha15-20%mortality

AcuteGvHD 100DaySurvivalGradeI 78-90%GradeII 66-92%GradeIII 29-62%GradeIV 23-25%

Preven3on/ControlofaGvHDIsImportant

(Przepiorkaetal,1995)

•  Prophylaxis–Preven3onofaGvHD•  Treatment–TherapyofaGvHD

Pa)ent

AllogeneicBMT

RegularChemo±XRT

HighdoseChemo±

XRT

14-21days

Time

Donor

AcuteGvHDProphylaxis

•  Micromethotrexate•  Posttransplantcyclophosphamide•  AlphabetaTcelldeple3onandCD34selec3on

AcuteGvHDProphylaxis–µMTX

•  Prophylaxiswithtacrolimus(TAC),mycophe-nolatemofe3l(MMF),andmethotrexate

•  Methotrexate(2.5mg/m2isgivenondays1,3,6•  MMFisgivenfromday-1un3lday60•  TACisgivenfromday-1un3lday100.Atday100taperingbeginsun3lday180whenitisstopped.

•  21%ofpa3entsdevelopaGvHDdespiteprophylaxis

MMF and tacrolimus

Methotrexate

Graft

-2 -1 0 1 2 3 4 5 6 7 8 Day

TACandMMFCondi)oning

MMF and tacrolimus

Methotrexate

Graft

-2 -1 0 1 2 3 4 5 6 7 8 Day


MMF and tacrolimus

Methotrexate

Graft

-2 -1 0 1 2 3 4 5 6 7 8 Day


Donorcellprolifera3on

MMF and tacrolimus

Methotrexate

Graft

-2 -1 0 1 2 3 4 5 6 7 8 Day

TACandMMF

MTX

Condi)oning


MMF and tacrolimus

Methotrexate

Graft

-2 -1 0 1 2 3 4 5 6 7 8 Day

TACandMMF

MTX

Condi)oning


MMF and tacrolimus

Methotrexate

Graft

-2 -1 0 1 2 3 4 5 6 7 8 Day

TACandMMF

MTX MTX

Condi)oning


MMF and tacrolimus

Methotrexate

Graft

-2 -1 0 1 2 3 4 5 6 7 8 Day

TACandMMF

MTX MTX MTX

Condi)oning

Tcellprolifera3on


•  Micromethotrexate•  Posttransplantcyclophosphamide

Cyclophosphamide


CytochromeP450

Aldophosphamide


Acrolein(ac3ve)



Tautomer-iza3on

ElevatedinstemcellsHigherinresAnglymphocytesversusacAvatedlymphocytes

MMF and tacrolimus

High dose CY

Graft

-6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 Day

TACandMMF

FLU-CY-TBI

MMF and tacrolimus

High dose CY

Graft

-6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 Day

TACandMMF

FLU-CY-TBI

MMF and tacrolimus

High dose CY

Graft

-6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 Day

TACandMMF

FLU-CY-TBI

Tcellprolifera3on

MMF and tacrolimus

High dose CY

Graft

-6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 Day

TACandMMF

CY

FLU-CY-TBI

Tcellprolifera3on

MMF and tacrolimus

High dose CY

Graft

-6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 Day

TACandMMF

CY

FLU-CY-TBI

Tcellprolifera3on

Highdosecyclophosphamide

-6-5-4-3-2-1012345678 Day

TACandMMF

CY

FLU-CY-TBI

RegularTherapy

14-21d

Pa)ent

Time

Donor


-6-5-4-3-2-1012345678 Day

TACandMMF

CY

FLU-CY-TBI

RegularTherapy

14-21d

Pa)ent

Time

Donor


-6-5-4-3-2-1012345678 Day

TACandMMF

CY

FLU-CY-TBI

RegularTherapy

14-21d

Pa)ent

Time

Donor


-6-5-4-3-2-1012345678 Day

TACandMMF

CY

FLU-CY-TBI

RegularTherapy

14-21d

Pa)ent

Time

Donor

PostHCTcyclophosphamide(Cy)forGvHDDay0

76

PostHCTcyclophosphamide(Cy)forGvHD

77


78

PostHCTcyclophosphamide(Cy)forGvHDCy Cy

79

PostHCTcyclophosphamide(Cy)forGvHDCy Cy

XX 80


81


J

J

82


•  Micromethotrexate•  Posttransplantcyclophosphamide•  AlphabetaTcelldeple3onandCD34selec3on

RPCIProphylaxisRegimensPt-Cy uMTX

Ac)veagent Cyclophosphamide Methotrexate

Target Prolifera)ngTcells Prolifera)ngTcellsPlaceofac)on Invivo Invivo

Tcell Deple)on Deple)on

Other TacroCellcept

TacroCellcept

84

HCTforhematologicmalignancyHaplo* Standard#

Condi)oning Flu/Cy/TBI Flu/Mel/TBI

aGvHDprophylaxis Cy/Tac/MMF uMTX/Tac/MMF

GraNfailure 6% 0%

aGvHDGr.III-IV 3%(day180) 27%(day100)

Progressionfreesurvival 37%(3years) 44%(2years)

Overallsurvival 46%(3years) 47%(2years)*Kasamon,etal.JCO2015,#RPCIunpublisheddata 85


•  HowdoesBillingham’shypothesisexplainhowpost-transplantcyclophosphamidepreventsacutegraN-versus-hostdisease?

• WhatpropertydoescyclophosphamidehavethatenablesitsuseaNertransplantwithoutendangeringthegraN?

ChronicGraN-versus-HostDisease•  Posttransplantcomplica)onusuallyoccurring>100dayscharacterizedby–  Fibro)cskindisease– Dryandgrimymoutheyesduetoglandulardestruc)on

– Gastrointes)nalfibrosiswithmalnutri)on

•  50%oflongtermsurvivorswilldevelopsomeformofcGvHD

•  ChronicGvHDisthemajorcauseoflongtermmortalityotherthanrelapseaNertransplant

C

B

C

D

D




Chimera

htp://www.theoi.com/Tartaros/Khimaira.html

KHIMAIRA(Greek)wasathreeheaded,fire-breathingcreaturewiththefore-partsofalion,thehindquartersofagoat,andthetailofaserpent.TheChimerawasslainbyBellerophonastridePegasus.

DonorChimerism

RICorNMARx

14-21days Time

Removeimmuno-suppressionDonorlymphocyteinfusion

Mixed

Full

≥95%=Fullchimerism

Documents

Introduc)on to Clinical Hematopoie)c Cell Transplantaon (HCT)