成人急性淋巴细胞白血病的治疗.ppt

成人急性淋巴细胞白血病的治疗 ALL化学治疗诱导治疗自发缓解VCR Pred VP 诱导 CR36 67 VCR DNR Pred VDP 诱导 CR70 85 VCR DNR L Asp Pred VDLP 缓解期延长VCR DNR CTX Pred VDCP 缓解后治疗T ALL 大剂量CTX冲击 Ara C成熟B ALL 短疗程诱导及强化治疗中枢系统白血病的预防及治疗 RemissionInductionRegimensAndPostremissionTherapyforALLNo ofCNSSurvivalReferencepatientsInductionConsolidationMaintenanceProphylaxisCR Med mo Blood368V P D Cy Dex V Dox Cy6 MP MTXMTX XRT742871 123 1988Ara c 6 MPAra C TGBlood168V P Dox CyAra C MTX TGV P Dox 6 MPMTX681873 87 1989V P A CyMTX ActD CyBCNUBlood109V P A DV P A D6 MP MTXMTX XRT882878 2814 1991Ara c VM26 MTXLeukemia541V P D AV P Mito 6 MP MTXMTX80NR6 182 1992 CyV Dex MTX VM26 Ara CBlood197V P A D CyCy Ara c 6 MP V6 MP MTXMTX XRT853685 78 2814 1995A Dox Dex TGV PBlood128Cy V Dox DexMTX Ara C6 MP MTX V PMTX Ara C913686 173a 1995 GroupYearn pts Age InductionConsolidationMaintenanceCRLFSStudieswith 500patientsGMALL02 84199356228V P A D C AC M MPV DX AD AC C TG VMMP M75 39 at7yFGTALL199358133V P D R C AD AC AD AC AMP M V C P AD AC76 30 at10yMRC UKALLXA31997618 15V P A D AC VP D TG MP M V P82 28 at5yMRC ECOG41999920V P D A C AC MPHDM A AC VP V DX MP M V P89 D C TG SCTGMALL05 9352001116335V P A D C AC M MPV DX AD AC C TG VM MP M83 AC HDM A C HDAC Mi GIMEMA02886200279428V P A D C HDAC Mi V HDM HDAC DX VMMP M V AC Mi VM 82 29 at9yHDAC HDM DX Total463882 31 weightedmean Resultsofadultacutelymphoblasticleukemia ALL studies 1 DieterHoelzer etal Hematology 2002164 191 Resultsofadultacutelymphoblasticleukemia ALL studies 2 GroupYearn pts Age InductionConsolidationMaintenanceCRLFSRecentStudieswith 100patientsPethemaALL 937199810828V P D A CHDM V D P A C VM ACMP M V P Mi 86 41 at4yA C VM AC CALGB8199819835V P D A CC MP AC V A M AD DX TG PMP M V P85 36 at3ySweden9199912044HDAC C D V BXAD HDAC V BX C D n r 85 36 at3yVP SCTMDACC10200020439V AD DX CHDM HDAC C PMP M V P91 38 at5yLombardia11200112135I V A P C I V C VM HDAC HDM MP M84 49 at3yDX SCTNetherlands12200119333StandardHDAC VP16 allo autoSC 82 35 at5yTotal94486 38 weightedmean DieterHoelzer etal Hematology 2002164 191 CancerandLeukemiaGroupB CALGB Study8811 1 CourseI Induction 4wk CTXIV1200mg m2Day1DNRIV45mg m2Days1 2 3VCRIV2mgDays1 8 15 22PredPO60mg m2Days1 21L AspSC6000IU m2Days5 8 11 15 18 22Forpatients 60yroldCTX800mg m2Days1DNR30mg m2Days1 2 3Pred60mg m2Days1 7 LarsonRA etal Blood 85 2025 2037 CALGB8811 2 CourseII Earlyintensification 4wk repeatonce MTXIT15mgDay1CTXIV1000mg m2Day16 MPPO60mg m2 dDays1 14Ara CSC75mg m2 dDays1 4 8 11VCRIV2mgDays15 22L AspSC6000IU m2Days15 18 22 25CourseIII CNSprophylaxisandinterimmaintenance 12wk Cranialirradiation2400cGyDays1 12MTXIT15mgDays1 8 15 22 296 MPPO60mg m2 dDays1 70MTXPO20mg m2Days36 43 50 57 64 CALGB8811 3 CourseIV Lateintensification 8wk ADRIV30mg m2Days1 8 15VCRIV2mgDays1 8 15DEXPO10mg m2 dDays1 14CTXIV1000mg m2 dDay296 TGPO60mg m2 dDays29 42Ara CSC75mg m2 dDays29 32 36 39CourseV Prolongedmaintenance until24mofromdiagnosis VCRIV2mgDay1ofevery4wkPredPO60mg m2 dDays1 5ofevery4wkMTXPO20mg m2Days1 8 15 226 MPPO60mg m2 dDays1 28 CALGB8811 4 ResultsofTherapyPatients214Patientseligible197Inductiondeath17 9 Refractorydisease13 7 CR167 85 Diedinremission10 6 CensoredforBMTin1stCR5 3 Relapsed77 46 CCR75 45 CALGB8811 5 ResultsoftherapyRemissionDurationSurvivalCRMedianProbabilityofCCRMedianProbabilityofSurvivalVariablen n p mo at3yr 95 CI p mo at3yr 95 pTotal197165 85 290 46 0 37 0 55 360 50 0 42 0 50 CR167 45Age yr 3087 44 82 94 0 01360 51 0 38 0 63 0 21 420 69 0 57 0 68 0 0130 5992 47 78 85 250 43 0 39 0 57 250 39 0 28 0 51 6018 9 7 39 120 43 0 16 0 75 10 17 0 06 0 39 Leucocytes 30 000130 66 115 88 0 06370 51 0 40 0 62 0 05 440 59 0 49 0 68 0 001 30 00066 34 51 77 190 36 0 22 0 53 190 34 0 23 0 47 FABL171 37 64 90 0 35380 54 0 39 0 68 0 16 440 63 0 50 0 74 0 03L287 46 73 84 260 46 0 33 0 59 250 45 0 34 0 57 L38 4 6 75 30 17 0 03 0 56 60 38 0 11 0 74 CALGB8811 6 ResultsoftherapyRemissionDurationSurvivalCRMedianProbabilityofCCRMedianProbabilityofSurvivalVariablen n p mo at3yr 95 CI p mo at3yr 95 pImmunophenotypesB67 48 55 82 0 02250 42 0 27 0 58 0 14190 36 0 25 0 49 0 004T31 22 31 100 280 57 0 37 0 76 400 67 0 47 0 82 BMy19 14 14 74 270 38 0 18 0 64 270 47 0 26 0 69 TMy8 6 7 88 400 86 0 49 0 97 400 75 0 41 0 93 Other15 11 13 87 310 53 0 28 0 76 430 60 0 36 0 80 B BMy86 61 69 80 0 01250 41 0 28 0 55 210 38 0 28 0 50 0 001T TMy39 28 38 97 320 63 0 44 0 78 400 69 0 51 0 82 CytogeneticsandMolecularPh orBCR ABL 3021 70 0 1170 11 0 04 0 28 110 16 0 07 0 32 0 001Negativeby1test8370 84 330 56 0 43 0 69 440 45 0 45 0 67 Negativebybothtest2925 86 400 72 0 51 0 86 400 62 0 44 0 78 TreatmentResultsinAdultBurkitt typeL3ALLReferenceNInductionContinuationCR LFS SFOP17C V P DoxV P7658Bailliere sClinOncolMTX3 8gMTX8g7 339 1994CTX0 5 1gAra C3gMDACC13V Dox DexMTX1g8546ProcASCO 14 339 1995Ara C1 8gAra C3gGMALL24C Ara C VM PC Ara C P6350Blood 87 495 1996MTX0 5gMTX0 5g35V Ifo VM Ara CV C Ara C Dex7471Dex MTX1 5gMTX1 5gCALGB24V Ifo VP Ara CC V Dox Ara C7566ProcASCO 16 24a 1997Dex MTX1 5gMTX1 5g B NHL 86protocolforB cellALL TreatmentofB cellALLB NHL86protocolPretreatmentWBC 25 000 l orlargetumormassPred60mg m2 PO5daysCTX200mg m2 IVToavoidtumorlysissyndromeandcorrectpossiblemetabolicdisturbanceCycleAGivenatweek1 7 13MTX15mg Ara C40mg Dex4mg IT day1VCR2mg IV day1MTX1500mg m2 24hINF day1IFO800mg m2 IV days1 5 VM26100mg m2 days4 5Ara C150mg m2 q12h IV days4 5Dex10mg m2 PO days1 5 HoelzerD etal Blood 87 495 1996 CycleBGivenatweek4 10 16MTX15mg Ara C40mg Dex4mg IT day1VCR2mg IV day1MTX1500mg m2 24hINF day1CTX200mg m2 IV days1 5 ADR25mg m2 days4 5Dex10mg m2 PO days1 5CNSProphylaxisandTreatmentMTX Ara C DextripleintrathecaltherapyIrradiation24Gy givenweeks5 7withoutCNSinvolvement cranialirradiationwithCNSinvolvement cranialandspinalirradiation RiskGroupsinprecursor BandT lineageALLGoodRisk bothBandT lineageALLwithallofthefollowingfeaturesNoadversecytogeneticabnormalitiesAge 30yearsWBCcountatpresentation 30 000 LAchieveCRin 4 6weeksIntermediateRisk ALLwithprognosisfeaturesofneithergoodnorpoorriskgroupPoorRisk ALLwithanyofthefollowingprognosisfeatures Age 60yearsPrecursor BwithWBCcount 30 000 lAdverseCytogenetics t 9 22 t 4 11 ortrisomy8AchievmentoflateCR 4 6weekspostinduction 高危成人ALL的治疗t 4 11 ALL发生率 儿童ALL2 5 婴儿42 66 成人3 6 免疫表型 主要为早期B前体细胞 前前B HLA DR CD19 CD22 CD79a阳性 CD10阴性 59 患者共表达髓系抗原CD15和CDw65 临床特点 女性多见 60 高白细胞 预后差 儿童LES仅为9 19 成人缓解期小于1年 治疗要点 早期强化 Ara C3g m2 days1 4 Mito10mg m2 days2 6 CR1期异基因骨髓移植 两者LFS分别为48 60 t 9 22 ALL化疗CR率不低 但缓解期短 应尽早行Allo BMT SchochC etal Annhematol 70 195 1995 CNS白血病初诊时CNS白血病发生率 成人ALL6T cellALL8成熟B cellALL13CNS白血病复发率 无预防治疗30 29 32 鞘注化疗13 8 19 颅脑照射24Gy9 3 19 大剂量化疗14 10 16 大剂量化疗 鞘注7 2 16 大剂量化疗 鞘注 颅脑照射6 1 13 SalvageregimensinrelapsedorrefractoryadultALLMedianStudyTherapyNCR CR Survival mos A Vincristine steroid anthracyclinesCancerTreatRep 63 1413 1979V Dox Pred10407 JClinOncol 8 994 1990V Dox Dex64396 5 5 3Leukemia 11 2039 1997V Dox Dex CTX664412 8BrJHematol 97 86 1997V IDA Pred BMT61562 B MTX ASPCancer 43 1089 1979Asp MTX12337 Blood 59 334 1982MTX V Asp Dex14797 5 11 2AmJHematol 4 173 1978V P Dox Asp23694 7CancerTreatRep 65 83 1981Asp MTX26584 Asp MTX Ifo11553 3 SalvageRegimensinRelapsedorRefractoryadultALLMedianStudyTherapyNCR CR Survival mos C High doseAra C HDAC AmJMed 81 387 1986HDAC21382 3 5Leukemia 4 637 1990Mito HDAC24503 5 Cancer 65 5 1990Mito HDAC21382 3 5Blood 72 433 1988Amsa HDAC40724 Cancer 72 2155 1993Flud HDAC30305 5 3LeukLymph 25 579 1997Flud Ara C G CSF1283 ProcASCO 6 147 1987HDAC16506 成人ALLHSCT治疗 在过去的10年里 成人ALL的治疗取得了显著的进步 较大的多中心研究中CR率75 89 LFS28 39 在ALL预后良好亚型的治疗上取得了较大的进步 如T ALL或成熟B ALL LFS 50 而Ph BCR ABL阳性ALL的LFS 20 预后因素用于危险分层 并根据其亚组分型和复发危险进行个体化治疗至关重要 HSCT可以使高危或复发或未缓解的病人获得延长的LDF 5 1 1ALLinFirstremission 通过衡量移植相关死亡率与单独标准化疗的治愈率 allo HSCT作为诱导后治疗对标准化疗后的高危复发病人是有利的 StudyNDFSwithallogeneicHSCT DFSwithautograftorchemo PValueHovon18 56 12453360 05UKALL Ph 57 43454340 04UKALL Ph 58 14841a27a0 5LALA87 9 25746a31a0 04IBMTR 59 7193432NSJapaneseStudy 60 29053b30b0 02BGMT1206826 0 01 ComparativestudiesofAllogeneicHSCTinadults 15yrs withALLinfirstCR aOverallsurvival bAge30 1 2ALLinSecondremission IBMTR1991 1997资料显示CR2移植病人的DFS是42 K Wheeler等研究表明Allo HSCT5年DFS增加了14 from26 4 to40 7 K Wheeler etal Comparisonofbonemarrowtransplantandchemotherapyforrelapsedchildhoodacutelymphoblasticleukaemia theMRCUKALLXexperience MedicalResearchCouncilWorkingPartyonChildhoodLeukaemia Br J Haematol 101 1998 pp 94 103 1 3ALLinprimaryinductionfailureorsecondrelapse 初次诱导失败的病人很少被随后的化疗所治愈 HSCT能够治愈其中的10 20 HoelzerD etal Follow upofthefirsttwosuccessiveGermanmulticentretrialsforadultALL 01 81and02 84 GermanAdultALLStudyGroup Leukemia 1993 7 Suppl2 S130 4 2 Thieba