20098

HLA

monograph Vol.17

HLA

HLA

1

3

HLA4

HLA15

HVGHLA2-36

GVHHLA2-3HLA 7

10

15

HLA

3

HLA1970HLAHLAHLA1980HLAHLA-A,-B,-DR2GVHD1-4GVHDHLAHLAHLAHLA

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HLAHLAHLAHLAHLAhaploidentical transplantationHLAHLA-A,-B,-DRGVHGVHDHVG2HVGGVHhomozygousHLAB#CD#5HLAHLA1BB#HVGHLA2-3CGVHHLA2-3DD#HLAHLA

HVG

0 1 2 3

GVH

0 A B# C C

1 B B C C

2 D D D D#

3 D D D D

HLA

5

HLA1HLA1BB#HLAHLA1HLAHLA: A1

HLA1HLAIIIGVHD31%vs9%,P

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6

HVGHLA2-3HLAGVH1HVG23CHLAHLA1: C1

HLAGVH1HVG23CGVHDHLA1GVHDreduced-intensityconditioning,RIC7

HLA

7

GVHHLA2-3HLAHLAGVH23DD#HLA-A,-B,-DR1HLA: C1

1HLAGVH23DD#GVHDTHLAT1TexvivoT

CD349-13

2alemtuzumabATGTinvivoT7-11

3NIMA14,15

4GVHD16-18

5exvivoanergyinduction19,exvivoalloreactivecelldepletion

T1234GVL1exvivoTGVHD20HLAHLAGVHD

2123HLA

HLA-A,-B,-DRGVH1

4HLA-A,-B,DR

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HLA-A,-B,-DRB11

HLA-A,-B,-DR1HLA

31IPSSLowINT-11

4HLA

4.1 HLA10-12,21,22

4.2 SeattleT269HVGHLA-BHLA-DR64%1

4.3 OKT3partialT-celldepletion303023

4.4 PerugiaCD34G-CSFG-CSF24

4.5 Columbia1525HVGHLA34539%20%13%0%25

HLA

9

1

CML

CP1 GNR

AML,ALL

CR1 GNR

>CP2 Dev >CR2 Dev

AP Dev nonCR Dev

BC Dev

MDS

low GNR

lymphoma

CR GNR

INT1 GNR Sensitiverelapse GNR

INT2 Dev Resistantrelapse Dev

high Dev Post-autologousSCTrelapse Dev

SstandardofcareQOL

COclinicaloption

Devdevelopmental

GNRgenerallynotrecommended

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1Seattle 1-4, 26GVHDmethotrexateMTXSeattleHLAIIGVHD34%HLA384%GVHDcyclosporineCSP+MTXHLAGVHDHLA1IIGVHD10%HLA12-3PowlesGVHDCSPHLA1-335GVHD29%80%3512GVHDHLA2-3GVHD

2IBMTR 8Szydlo198519912055IBMTRHLA1224HLA12382102HLA383HLA1108HLA49%39%THLA2IIGVHDIIIGVHD16%56%36%HLA2320-25%HLA1HLA1HLA

33.1Columbia 21, 25, 27, 28

Henslee-Downey1990THLATBIcyclophosphamideetoposidecytarabineATGGVHDTCSPATG1993199920192%HLA2-398%IIGVHD13%519%18%

3.2Perugia 9-13AversaCD34HLAfludarabinethiotepaTBIATGNK19992004104AML67ALL37IIGVHD10082AML48%ALL46%4%RuggeriAMLHLA112NKalloreactivityKIRligandKIRligand

HLA

11

3%vs47%34%vs6%KIRligandNKalloreactivity

3.3Tuebingen 29-31 32, 33HandgretingerexvivoTCD34CD133CD3rituximabCD3/19CD34ALL/CD34or13328348%TuebingenHLAfludarabinethiotepamelphalanOKT-3TCD35x104/kgGVHDMMF29159

3.4Duke 34RizzierialemtuzumabinvivoTfludarabinecyclophosphamidealemtuzumabGVHDCSPMMFMMF493142IIIGVHD8%4131%63%

3.5Johns Hopkins 35, 36LuznikcyclophosphamideTfludarabinecyclophosphamideTBI2Gyday3day3,4cyclophosphamide50mg/kgTACtacrolimusMMFGVHD67PNH1669IIIGVHD6%236%26%

3.6 22, 37 38LuHLA158HLA135121262352cytarabinebusulfancyclophosphamideMe-CCNU1-2-chloroethyl-3-4-methylcyclohexyl-1-nitrosourea,semustineHLAATGG-CSFGVHCSPMTXMMF22GradeII-IVGVHDHLA32%HLA402HLAHLA14%vs2213%vs1871%vs6472%vs71advancedstage247

3.7HarvardSykescyclophosphamidefludarabineCD2GVHD

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12

39-42HarvardGuinanTanergyHLA19TCTLA-4-Iganergy11GVHD3

44.1CD34HLA 43

CD34135HLA0-12826434312812027IIGVHD212278395.7

4.2HLA 6HLA294711122-330HLAHLA1HLA

4.3HLA2-3 44GVHHLA2-3501832CD341n=3326n=1020n=7196156%30%

4.4HLA 7HLA3411572-3342GVHDHLA39%144%2-350%2HLA48%151%2-318%HLA1HLA

4.5NIMAHLA 14, 15HLAHLA2-3HLAexvivoTHLAnon-inheritedmaternalHLAantigens,NIMAHLA2-3TAC,MTXGVHDTIIGVHD3

HLA

13

1635NIMA3419IIGVHDIII8IIIGVHD338%

4.6alemtuzumabHLA 45HLA1HLAalemtuzumabHLACyclophosphamideTBIalemtuzumab0.2mg/kg/day655fludarabinebusulfanalemtuzumab185427602731118IIIGVHD1alemtuzumabGVHD23HLATGanciclovirGVHDHLAGVTHLAGVHDalemtuzumab200412alemtuzumab0.2mg/kg/day63alemtuzumab0.16mg/kg/day63CRMContinualReassessmentMethodalemtuzumab

4.7/HLA2-3 16-18HLA3026fludarabinecyclophosphamideTBI8-10GycytarabineGVHDTACMTXMMFmPSL2mg/kgIIGVHD36.7%IIIGVHD10%349.9%fludarabinebusulfanATGGVHDTACmPSL1mg/kg1IIGVHD20%IIIGVHD355.0%

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InfectiousDiseasesSocietyofAmerica;IDSAUnitedStatesPublicHealthService

ABCDE

2 case-control

HLA

15

1BeattyPG,CliftRA,MickelsonEM,etal.MarrowtransplantationfromrelateddonorsotherthanHLA-identicalsiblings.NEnglJMed.1985;313:765-771.

2AnasettiC,AmosD,BeattyPG,etal.EffectofHLAcompatibilityonengraftmentofbonemarrowtransplantsinpatientswithleukemiaorlymphoma.NEnglJMed.1989;320:197-204.

3AnasettiC,BeattyPG,StorbR,etal.EffectofHLAincompatibilityongraft-versus-hostdisease,relapse,andsurvivalaftermarrowtransplantationforpatientswithleukemiaorlymphoma.HumImmunol.1990;29:79-91.

4AnasettiC.Theroleoftheimmunogeneticslaboratoryinmarrowtransplantation.ArchPatholLabMed.1991;115:288-292.

5AnasettiC,HansenJA.BonemarrowtransplantationfromHLA-partiallymatchedrelateddonorsandunrelatedvolunteerdonors.Boston:BlackwellScience;1994.

6KandaY,ChibaS,HiraiH, et al.Allogeneichematopoietic stemcell transplantation fromfamilymembersother thanHLA-identical siblingsover the lastdecade1991-2000.Blood.2003;102:1541-1547.

7TeshimaT,MatsuoK,MatsueK,etal. Impactofhuman leucocyteantigenmismatchongraft-versus-hostdiseaseandgraftfailureafterreducedintensityconditioningallogeneichaematopoieticstemcelltransplantationfromrelateddonors.BrJHaematol.2005;130:575-587.

8SzydloR,GoldmanJM,KleinJP,etal.ResultsofallogeneicbonemarrowtransplantsforleukemiausingdonorsotherthanHLA-identicalsiblings.JClinOncol.1997;15:1767-1777.

9AversaF,TabilioA,TerenziA,etal.SuccessfulengraftmentofT-cell-depletedhaploidentical"three-loci" incompatible transplants in leukemiapatientsbyadditionof recombinanthumangranulocytecolony-stimulatingfactor-mobilizedperipheralbloodprogenitorcellstobonemarrowinoculum.Blood.1994;84:3948-3955.

10AversaF,TabilioA,VelardiA,etal.Treatmentofhigh-riskacute leukemiawithT-cell-depletedstemcells from relateddonorswithone fullymismatchedHLAhaplotype.NEngl JMed.1998;339:1186-1193.

11RuggeriL,CapanniM,UrbaniE,etal.Effectivenessofdonornaturalkillercellalloreactivityinmismatchedhematopoietictransplants.Science.2002;295:2097-2100.

12AversaF,TerenziA,TabilioA, et al. Full haplotype-mismatchedhematopoietic stem-celltransplantation:aphaseIIstudy inpatientswithacute leukemiaathighriskofrelapse.JClinOncol.2005;23:3447-3454.

13RuggeriL,MancusiA,CapanniM,etal.Donornaturalkillercellallorecognitionofmissingselfinhaploidenticalhematopoietictransplantationforacutemyeloidleukemia:challengingitspredictivevalue.Blood.2007;110:433-440.

14ShimazakiC,OchiaiN,UchidaR, et al.Non-T-cell depletedHLAhaploidentical stemcell transplantation in advanced hematologicalmalignancies based on the feto-maternalmicrochimerism.Blood.2003;101:3334-3336.

15IchinoheT,UchiyamaT,ShimazakiC,etal.FeasibilityofHLA-haploidenticalhematopoieticstemcelltransplantationbetweennoninheritedmaternalantigenNIMA-mismatchedfamilymemberslinkedwithlong-termfetomaternalmicrochimerism.Blood.2004;104:3821-3828.

16OgawaH,IkegameK,KaidaK,etal.UnmanipulatedHLA2-3antigen-mismatchedhaploidenticalbonemarrow transplantationusingonlypharmacologicalGVHDprophylaxis.ExpHematol.2008;36:1-8.

17OgawaH, IkegameK,KawakamiM,etal.Powerfulgraft-versus-leukemiaeffectsexertedby

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HLA-haploidentical grafts engraftedwitha reduced-intensity regimen for relapse followingmyeloablativeHLA-matchedtransplantation.Transplantation.2004;78:488-489.

18OgawaH, IkegameK,Yoshihara S, et al.UnmanipulatedHLA2-3 antigen-mismatchedhaploidenticalstemcelltransplantationusingnonmyeloablativeconditioning.BiolBloodMarrowTransplant.2006;12:1073-1084.

19GuinanEC,BoussiotisVA,NeubergD,etal.Transplantationofanergichistoincompatiblebonemarrowallografts.NEnglJMed.1999;340:1704-1714.

20OhH,LoberizaFR,Jr.,ZhangMJ,etal.Comparisonofgraft-versus-host-diseaseandsurvivalafterHLA-identicalsiblingbonemarrowtransplantationinethnicpopulations.Blood.2005;105:1408-1416.

21Henslee-DowneyPJ,AbhyankarSH,ParrishRS,etal.Useofpartiallymismatchedrelateddonorsextendsaccesstoallogeneicmarrowtransplant.Blood.1997;89:3864-3872.

22LuDP,DongL,WuT, et al.Conditioning including antithymocyte globulin followedbyunmanipulatedHLA-mismatched/haploidenticalbloodandmarrowtransplantationcanachievecomparableoutcomeswithHLA-identicalsiblingtransplantation.Blood.2006;107:3065-3073.

23GodderKT,HazlettLJ,AbhyankarSH,etal.Partiallymismatchedrelated-donorbonemarrowtransplantation forpediatric patientswith acute leukemia: youngerdonors andabsenceofperipheralblastsimproveoutcome.JClinOncol.2000;18:1856-1866.

24VolpiI,PerruccioK,TostiA,etal.Postgraftingadministrationofgranulocytecolony-stimulatingfactor impairs functional immunerecovery inrecipientsofhumanleukocyteantigenhaplotype-mismatchedhematopoietictransplants.Blood.2001;97:2514-2521.

25MehtaJ,SinghalS,GeeAP,etal.BonemarrowtransplantationfrompartiallyHLA-mismatchedfamilydonors for acute leukemia: single-center experienceof 201patients.BoneMarrowTransplant.2004;33:389-396.

26PowlesRL,MorgensternGR,KayHE, et al.Mismatched family donors for bone-marrowtransplantationastreatmentforacuteleukaemia.Lancet.1983;1:612-615.

27SinghalS,PowlesR,Henslee-DowneyPJ,etal.Allogeneic transplantationfromHLA-matchedsiblingorpartiallyHLA-mismatchedrelateddonorsforprimaryrefractoryacute leukemia.BoneMarrowTransplant.2002;29:291-295.

28SinghalS,Henslee-DowneyPJ,PowlesR,etal.Haploidenticalvsautologoushematopoieticstemcell transplantation inpatientswithacute leukemiabeyondfirst rem