成人急性淋巴细胞白血病的治疗-2017 ASH点滴

成人急性淋巴细胞白血病的治疗

——2017ASH点滴InductionConsolidation/IntensificatonMaintenanceCNSProphylaxisVincristineAnthracyclineCorticosteroidL-AsparaginaseHyper-CVAD目的：尽快恢复正常造血Hyper-CVAD(hyperfractionatedCTX,alternatingwithhigh-dosecytarabine/methotrexate)……SCT目的：巩固疗效、清除MRD目的：维持治疗反应、延长DFS6-MercaptopurineMethotrexateVincristine/prednisone

成人ALL治疗的一般原则(整体综合治疗)靶向治疗细胞免疫治疗(CAR-T)采用儿童方案治疗成人ALL的临床试验中心年龄儿童方案的组成结果Dana-Farber18-50高危儿童ALL00-01方案(早期、2年EFS(美国)频繁的IT，强化非骨髓抑制性药物

72.5%

的应用-如ASP，早期强化、长期维持OS77.1%GRAALL15-60加强非骨髓抑制性药物的应用，晚期42个月(法国)强化，缩短诱导缓解和巩固治疗的间隔EFS50%OS60%芬兰白血病组17-25增加VCR和激素的应用，早期和频繁IT5年EFS

早期、晚期强化，长期维持、集中治疗60%OS70%MDACC13-83早期、频繁IT；早期和晚期强化3年OS

维持治疗60%PETHEMA15-30儿童ALL-96方案，早期和频繁IT；6年EFS(西班牙)加强非骨髓抑制性药物的应用；61%；早期强化、维持OS69%

(1)长春碱类:(2)蒽环类药物：用药剂量和用法。诱导治疗多为连续应用，如DNR30-60mg/m2/d2-3天；部分为每周用药一次的做法。

(3)地塞米松vs泼尼松：地塞米松有更强的抗白血病作用(?)，在脑脊液中浓度较高、维持半衰期长(易导致严重的败血症和真菌感染)。

(4)L-ASP：主要副作用—血栓并发症和高血糖。(MDACC的Hyper-CVAD方案中不含L-ASP)。(5)HD-MTX和阿糖胞苷(6)维持治疗用药：6-MP和MTXALL治疗常涉及的用药问题诱导治疗：一般以4周方案为基础。

至少应予长春新碱(VCR)或长春地辛、蒽环/蒽醌类药物(如柔红霉素-DNR、去甲氧柔红霉素-IDA、阿霉素、米托蒽醌等)、糖皮质激素(如泼尼松、地塞米松等)为基础的方案(VDP)诱导治疗。推荐采用VDP联合CTX和门冬酰胺酶(L-ASP)组成的VDCLP方案，鼓励开展临床研究。也可以采用Hyper-CVAD方案。TotalXIIIATotalXIIIBTotalXV(StJ)治疗周期120W120W120W(女)/145W(男)累积L-ASP

低危18万U/m212万U/m224万U/m2

标危/高危25万U/m212-15万U/m253.5-56.5万U/m2累积蒽环类

低危50mg/m2

100mg/m2

110mg/m2

标危/高危100mg/m2

230mg/m2

累积CTX低危—

—

1000mg/m2

标危/高危8400mg/m2

8700mg/m2

4600mg/m2

累积HD-MTX低危16-17g/m2

11g/m2

标危/高危4-5g/m2

20-21g/m2

21g/m2

成人ALL的进展—2017ASHState-of-the-artALLtharapyLearningfromthekidsMovingtowardsubset-specifictreatment:

rituximabandnelarabine.

Immunotherapies:

Blinatumomab,Inotuzumab

ozogamicin,CAR-TcellsNewbiologicalinsightsandtargetedtreatmentwillleadtobettertreatmentoutcomes.Ph-likeALLMovingimmunetargetingtothefrontline

ThegoalinmovinganytherapytothefrontlineshouldbetoenhanceratesofMRDnegativity,astheearlyeradicationofdiseaseseemstobeoneofthemostimportantfactorsinimpactingevent-freeandoverallsurvivalrates.StrategiesforthefutureLeonardJALL诱导治疗糖皮质激素应用地塞米松VS泼尼松(诱导治疗)—EORTCLeukemiaGroupPhaseIII临床试验(6年随访结果)Haematologica.2010评价指标地塞米松泼尼松

(8mg/m2)(60mg/m2)

n=163n=162

CR131(80.4%)124(76.5%)

DFS43(32.8%)46(37.1%)

复发

BM44(33.6%)48(38.7%)

CNS3(2.3%)5(4.0%)

CNS+BM6(4.6%)5(4.0%)

OS50(30.7%)58(35.8%)Ab141

UKALL2011:RandomisedTrialInvestigatingaShortInductionDexamethasoneScheduleforChildrenandYoungAdultswithAcuteLymphoblasticLeukaemiaGouldenNJ短诱导：地塞米松

5mg/m2，2次/天(10mg/m2/d)，14天(10岁以下连续14天，10岁以上用一周停一周)标准诱导：地塞米松3mg/m2，2次/天(6mg/m2/d)，连续29天，一周内减停。二.缓解后治疗(一)门冬酰胺酶的用药Ab1275

IntermittentVsContinuousAsparaginasetoReduceAsp-AssociatedToxicities:ANOPHOALL2008RandomizedStudyAlbertsenBK(丹麦)随机分组前：AllchildrenweretreatedwithfivedosesofPEG-asp1000IU/m2

i.m.attwoweeksintervalsfromtreatmentday30(endofinduction).后期强化(治疗的第92天)开始随机分组：Standardarm:continuousasparaginasetreatmentforanother10dosesat2wintervalsExperimentalarm:intermittentfor3dosesat6wintervals.Patientsintheexperimentalarmdidnotreceiveasparaginaseduringdexamethasonecontainingdelayedintensification.Hazardratio:experimentalarmversusstandardarmPancreatitissignificantlyreduced(p=0.017)AllergyforIRpatients(p=0.089)(noeffectforSRpatients)Thrombosissignificantlyreducedinboys(p=0.027)(noeffectforgirls).Nosignificantdifferenceswereobservedregardingosteonecrosis(ON)andinvasivefungalinfections.IntermittentratherthanacontinuousasparaginasetreatmentstrategyresultsinalmostidenticalEFSinnon-HRpatientswithlowercostsandamarkedlyreducedriskofserioustoxicities.(二)6-巯嘌呤和ALL治疗6-MPexertsitscytotoxicitythroughconversionintothioguaninenucleotides(TGN)thataresubstratesforDNApolymeraseandcompetewithnormalguanineforDNAincorporation.HigherlevelsofDNA-incorporatedTGNwereassociatedwithareducedrelapseriskinnon-highriskALLMercaptopurinecanbedirectlyanabolizedbythiopurinemethyltransferase(TPMT)totheinactivemethylmercaptopurine,andthiopurineactivemetabolitescanalsobecatabolizedviadephosphorylationofthioguaninenucleotides(TGN).6-MP代谢和耐受性(TPMT、NUDT多态性)YangJ.JClinOncol33:1235©2015TCandCCgenotypesMPdoseintensitywasdefinedastheratiobetweenclinician-prescribedMPdoseandprotocoldose(%).TPMT—thiopurinemethyltransferase,(T)1279

NoAssociationbetweenRelapseRiskandThiopurineMethyltransferaseActivityByEitherGeno-orPhenotypeintheNOPHOALL-2008ProtocolAb142Individualized6-MercaptopurineIncrementsinConsolidationTreatmentofChildhoodAcuteLymphoblasticLeukemia:ANOPHOALL2008RandomizedControlledTrialMortenTulstrupHypothesis:Individualized,toxicity-titrated6-mercaptopurine(6-MP)incrementsduringconsolidationtherapywithhigh-dosemethotrexateweresuperiortothestandardfixed-dose6-MPregimen.Theprimaryendpointwasminimalresidualdisease(MRD)positivityatendofconsolidation,andthesecondaryendpointwasevent-freesurvival.试验组：392例；

标准治疗组：396例标准治疗组：6-MP(25mg/m2/d)d30-85

试验组：

自d50和/或71开始逐步递增(25mg/m2/d)

剂量限制性毒性(骨髓抑制)：前一次(d36或57)HD-MTX用药后中性粒≤0.5x109/L或血小板<50x109/L)整个巩固治疗中监测血DNA-TGN和6-MP甲基化代谢产物(MeMP).试验组58%的患者6-MP剂量增加DNA-TGN水平和剂量增加直接相关和标准治疗组比较：试验组巩固治疗结束时MRD无明显改善；没有从6-MP剂量增加中有生存获益。Ab140

IntensificationofOralMethotrexateIsNotSuperiortoStandardMethotrexateDosingduringMaintenanceinChildrenwithNationalCancerInstitute(NCI)Standard-RiskBAcuteLymphoblasticLeukemia(SRB-ALL):AReportfromChildren’sOncologyGroup(COG)StudyAALL0932AnneAngiolillo比较MTX40mg/m²/dose/周与标准的20mg/m2/dose每12周予VCR/DEX和每4周用药对疗效的影响。(三)维持治疗EscalationoftheMTXstartingdosedoesnotimproveoutcome.ResultsfromtheVCR/DEXpulserandomizationremainblinded.Ab1284DecreasingDoseandDurationofDexamethasoneTherapyforLow-RiskChildhoodAcuteLymphoblasticLeukemiaAimingtoAvoidSeriousViralInfectionsResultsinSignificantIncreaseinIsolatedCNSRelapse:AProspectiveStudy——维持治疗Patientsontherapywhocompletedmorethanhalfoftheirplanneddexamethasonepulses(week50)wereassignedtogroup1.Patientswhohadreceivedlessthanhalfoftheirplanneddexamethasonepulses(week50)wereassignedtogroup2.StJudeTotalXVprotocol地塞米松剂量减少25%(由8mg减为6mg/m2/day,5days/week,every4weeks)维持治疗中地塞米松脉冲式用药：由100周减为69周。cumulativeincidence：孤立性CNSL复发三.整体治疗方案对疗效的影响Ab1323

IstheOutcomeofPatientswithHighRiskT-CellAcuteLymphoblasticLeukemiaImprovingintheEraofPediatric-InspiredProtocols?aComparisonof2ConsecutivePethemaTrialsPereBarba(Spain)TocomparetheoutcomeofpatientswithhighriskT-cellALLincludedin2consecutivetrialsoftheSpanishPETHEMAGroup(ALL-HR03[NCT00853008]andthemorecontemporaryALL-HR11[NCTNCT01540812]).ALL-HR03andALL-HR11trial均为儿童特点方案。ALL-HR11方案诱导治疗时DNR剂量较低、巩固治疗强度较弱

(只有MTX剂量由3g/m2增加为5g/m2)；体现根据流式MRD(诱导和巩固结束)决定Allo-SCT的理念。共169例T-ALL(HR03试验104例、随访期5.2年，HR11试验65例、随访期1.8年)两组CR率和DFS相似，HR11组的OS优于HR03组(HR11组治疗相关死亡率降低)Ab478

IntensifyingTreatmentinChildhoodB-ALLwith

IKZF1

DeletionsNegatesItsAdverseOutcome:ResultsofMa-SporeALL2003and2010StudiesYiLuIKZF1del

wasfoundin15.9%ofentiregroupand13.2%of

BCR-ABL1-negativecases.

IKZF1del

wasoverrepresentedin

BCR-ABL1-positive(70.6%)andB-other(21.8%).UpgradingthetreatmentriskgroupforchildrenwithB-LLand

IKZF1delnegatestheadverseoutcomeof

IKZF1del

particularlyforDay33MRD-positive(≥10-4)patients(MS2010)protocolupgradedpatientstothenexthighertreatmentriskgroupiftheycarry

IKZF1del.Ma-SporeALL2003protocol四.成人ALL的靶向治疗Ab2714

PersistenceoftheMinimalResidualDiseaseattheEndofInductionIsNotaFactorofPoorPrognosisIfImatinibWasChangedtotheDasatinibByPh+RALLProtocolinPh-PositiveAcuteLymphoblasticLeukemiaPatientsOlgaA.Gavrilina(Russia),

如果在第70天仍未取得MMR，IM换为达沙替尼。143

InotuzumabOzogamicininCombinationwithBosutinibforPatientswithRelapsedorRefractoryPh+ALLorCMLinLymphoidBlastPhaseNitinJain(MDACC)Ab1322

RuxolitiniborDasatinibinCombinationwithChemotherapyforPatientswithRelapsed/RefractoryPhiladelphia(Ph)-likeAcuteLymphoblasticLeukemia:APhaseI-IITrialNitinJain(MDACC)五.预后相关——MRD2017ASHAb139:

EvaluationofMinimalResidualDisease(MRD)andMRD-BasedTreatmentDecisionsinPh/BCR-ABLNegativeAdultAcuteLymphoblasticLeukemia(ALL):ExperiencefromtheGermanMulticenterStudyGroupforAdultALL(GMALL)NicolaGoekbugetProtocol07/03(withinthetrialorinGMALLregistry).MRDwastestedbyreal-timePCRofclonalTCRandIggenerearrangementsAnalysisreferstomolecularresponsein'wk16'afterinduction/1stconsolidationandtomolecularrelapse(MolR)laterthanwk16MolecularCR(MolCR):≤10-4Molecularfailure(MolF):>10-4MRDneg：MRD(-)，但敏感度不够MRDpos：detectable(MRD<10-4)或无定量MRDMolR：取得MolCR的患者在16W以后又出现MRD>10-4

MolCR

MolF

MRDneg

MRDpos

MolR

5年OS83%43%78%68%51%

5年CCR80%38%76%56%35%

121/196(62%)MolF患者在CR1行SCT

non-SCTSCT

5年OS28%53%

5年CCR9%56%

Ab