NKT细胞淋巴瘤周剑峰专家讲座

NK细胞增殖性疾病同济医院血液内科周剑峰2015年06月07日NKT细胞淋巴瘤周剑峰专家讲座第1页T和NK细胞肿瘤分类：WHOWHO:thematureT-cellandNK-cellneoplasmsT-cellprolymphocyticleukemiaT-celllargegranularlymphocyticleukemiaChroniclymphoproliferativedisorderofNK-cells*AggressiveNKcellleukemiaSystemicEBV+

T-celllymphoproliferativediseaseofchildhood(associatedwithCAEBV)Hydroavacciniforme-likelymphomaAdultT-cellleukemia/lymphomaExtranodalNK/Tcelllymphoma,nasaltypeEnteropathy-associated

T-celllymphomaHepatosplenicT-celllymphomaSubcutaneouspanniculitis-likeT-celllymphomaMycosisfungoidesSézarysyndromePrimarycutaneousCD30+

T-celllymphoproliferativedisorder    Lymphomatoidpapulosis    Primarycutaneousanaplasticlarge-celllymphomaPrimarycutaneousaggressiveepidermotropicCD8+

cytotoxicT-celllymphoma*Primarycutaneousgamma-deltaT-celllymphomaPrimarycutaneoussmall/mediumCD4+

T-celllymphoma*PeripheralT-celllymphoma,nototherwisespecifiedAngioimmunoblasticT-celllymphomaAnaplasticlargecelllymphoma(ALCL),ALK+Anaplasticlargecelllymphoma(ALCL),ALK−*NKT细胞淋巴瘤周剑峰专家讲座第2页WHOWHOCommentsAngioimmunoblasticLymphomaAngioimmunoblasticLymphomaDefinitionoforigincellAnaplasticLargeCellLymphoma2variantsbasedonALK(+/-)expressionPrognosticimportanceUnspecifiedPeripheralT-cellLymphomaPeripheralT-cellLymphomasnotOtherwiseSpecified3variants:lymphoepitelioidlymphoma,Tzonelymphoma(WHO)andfollicularlymphoma(WHO)T/NK-celllymphoma,nasaltypeT/NK-celllymphoma,nasaltypeNochangesEntheropathy-associatedT-celllymphomaEntheropathy-associatedT-celllymphomasTwovariants:classicalandmonomorphictypeswithgeneticchangescommontobothHepatosplenicT-celllymphomaHepatosplenicT-celllymphomaNochangesSubcutaneouspanniculitis-likeT-celllymphomaSubcutaneouspanniculitis-likeT-celllymphomaOnlyabandassociatedwithautoimmunedisorderMycosisfungoidesMycosisfungoidesNewstagingandnewinformationaboutpathogenesisSézarysyndromeSézarysyndromeNewmarkersPrimarycutaneousanaplasticlargecelllymphomaPrimarycutaneousanaplasticlargecelllymphomaRecognitionofCD8+casesLymphomatoidpapulosisLymphomatoidpapulosisThreehistologicaltypesPrimarycutaneousgamma-deltaT-celllymphomaThreehistopathologicpatterns:epidermotropic,dermic,andsubcutaneoussubtypesPrimarycutaneousCD8+aggressiveepidermotropiccytotoxicT-celllymphomaProvisionalentityPrimarycutaneousCD4+small/mediumT-celllymphomaProvisionalentityBlasticNK-celllymphomaPlasmocytoiddendriticcellneoplasmNowitisoneofthemyeloidneoplasmsT-cellprolymphocyticleukemiaT-cellprolymphocyticleukemiaNochangesT-celllargegranularlymphocyticleukemiaT-celllargegranularlymphocyticleukemiaNewetiologicalfeaturesandnewmarkersChroniclymphoproliferativedisorderofNK-cellsProvisionalentityAggressiveNK-cellleukemiaAggressiveNK-cellleukemiaNochangesAdultT-cellleukemia/lymphomaAdultT-cellleukemia/lymphomaDefinitionoftheregulatoryT-cellnormalcounterpartT和NK细胞肿瘤分类主要改变NKT细胞淋巴瘤周剑峰专家讲座第3页EBV相关淋巴增殖性疾病JKoreanMedSci.Apr;23(2):185-92.NKT细胞淋巴瘤周剑峰专家讲座第4页EBV相关T/NK细胞增殖性疾病JDermatol.;41(1):29-39.NKT细胞淋巴瘤周剑峰专家讲座第5页潜伏性感染，不是裂解式感染，抗病毒治疗无效NKT细胞淋巴瘤周剑峰专家讲座第6页NK/T细胞淋巴瘤NKT细胞淋巴瘤周剑峰专家讲座第7页NK/T细胞淋巴瘤亚型分布NK/T细胞淋巴瘤占到全部PTCL10.4%JClinOncol,,26(25):4124-30NKT细胞淋巴瘤周剑峰专家讲座第8页NKT细胞淋巴瘤周剑峰专家讲座第9页NK/T细胞淋巴瘤特征分为鼻型(68%)和非鼻型(26%),其它为侵袭型（6%）病理表现：形态多样，表现为血管中心性、大量坏死和血管浸润表型：大部分为NK细胞（EBV+，CD56+）NKT细胞淋巴瘤周剑峰专家讲座第10页鼻型与非鼻型NK/T细胞淋巴瘤鼻型非鼻型侵犯部位上呼吸皮肤、睾丸、胃肠道疾病晚期27%68%肿块>5cm12%68%超出2个鼻外病灶16%55%LDH升高45%60%B症状39%54%5年OS率42%9%中位OS19月4月NKT细胞淋巴瘤周剑峰专家讲座第11页鼻型与非鼻型NK/T细胞淋巴瘤Nasaltype:41%Non-nasal:22%Nasaltype:34%Non-nasal:13%AnnOncol;19:1477-1484NKT细胞淋巴瘤周剑峰专家讲座第12页放疗在NK/T细胞淋巴瘤中地位仅早期患者可作为根治伎俩，其余多数与化疗联用NKT细胞淋巴瘤周剑峰专家讲座第13页什么样NK/T细胞淋巴瘤能够单纯放疗？Nasal

versusextra-nasalthestageofthediseaseStageIdiseasearefurtherstratifiedbasedonriskfactorsAge≥60years,Bsymptoms,ECOGperformancestatus≥2RegionallymphnodeinvolvementLocaltumorinvasionElevatedLDHHighKi-67stainingEBVDNA≥6.1x107copies/mLNKT细胞淋巴瘤周剑峰专家讲座第14页更新了治疗方案后，化疗是必不可少治疗伎俩局限期鼻型NK/T细胞淋巴瘤单纯放疗RR和CR分别达78-94%和66-94%，但5y-OS和中位OS仅分别为35%-83%和50%患者出现皮肤、骨髓、睾丸、内脏和淋巴结侵犯较常见化疗依然是必不可少治疗伎俩NKT细胞淋巴瘤周剑峰专家讲座第15页NK/T细胞肿瘤含有不一样寻常表型特征NKT细胞淋巴瘤周剑峰专家讲座第16页含门冬酰胺酶方案NKT细胞淋巴瘤周剑峰专家讲座第17页SMILE方案Smile方案Steroid(DXM)40mg,iv,d2-4MTX2g/m2,iv,d1IFO1.5g/m2,iv,d2-4L-ASP6000U/m2,iv,d8,10,12,14,16,18,20Etopside100mg/m2,iv,d2-4G-CSF从第6天开始解救，wbc>5000/mlYamaguchiM,etal.JCO,;29(33):4410-6NKT细胞淋巴瘤周剑峰专家讲座第18页SMILE方案疗效及毒性CR率45%,CR+PR79%1y-OS55%毒性反应：92%患者出现IV度骨髓抑制，61%出现感染8%出现早期死亡YamaguchiM,etal.JCO,;29(33):4410-6NKT细胞淋巴瘤周剑峰专家讲座第19页AspaMetDex方案Steroid（DXM）,40mg,d1-4,poMTX3.0g/m2,d1,ivdripIFO1.5g/m2,iv,d2-4L-Asp6000U/m2,d2,4,6,8,imEtopside100mg/m2,iv,d2-4JaccardA,etal.Blood,,117:1834-1839.

Smile方案Steroid(DXM)40mg,iv,d2-4MTX2g/m2,iv,d1IFO1.5g/m2,iv,d2-4L-ASP6000U/m2,iv,d8,10,12,14,16,18,20Etopside100mg/m2,iv,d2-4NKT细胞淋巴瘤周剑峰专家讲座第20页近期疗效和毒性近期疗效18例可评价，14例取得缓解（78%），11例完全缓解（61%）3例治疗中死亡14例有效患者，6例在治疗结束后9个月内复发NKT细胞淋巴瘤周剑峰专家讲座第21页AspaMetDex方案

远期生存中位OS12.2个月无效患者4.2个月有效后进展患者3.6个月PFS12.2个月NKT细胞淋巴瘤周剑峰专家讲座第22页晚期结外NK/T细胞淋巴瘤治疗

GOLD方案Efficacyofgemcitabinecombinedwithoxaliplatin,L‑asparaginaseanddexamethasoneinpatientswithnewly‑diagnosedextranodalNK/T‑celllymphomaG：gemcitabine1g/m2，d1，D8O：Oxaliplatin100mg/m2，d1L：L-Asparaginase10,000U/m2，d1-5D：dexamethasone40mg，d1-414-daycycle，AnnArborI/II期化疗后给予IFRT-新诊疗ENKTLGuoHQ,LiuL,WangXF,LinTY,etal.MolClinOncol.Nov;2(6):1172-1176NKT细胞淋巴瘤周剑峰专家讲座第23页GOLD方案GuoHQ,LiuL,WangXF,LinTY,etal.MolClinOncol.Nov;2(6):1172-1176NKT细胞淋巴瘤周剑峰专家讲座第24页GOLD方案3YsPFS57%3YsOS74%1Ys

PFS87%vs66%P<0.0011Ys

OS98%vs75%P<0.001GuoHQ,LiuL,WangXF,LinTY,etal.MolClinOncol.Nov;2(6):1172-1176NKT细胞淋巴瘤周剑峰专家讲座第25页GOLD方案GOLD方案治疗ENKL取得很高ORR（91%），CR率62%，PR率29%3年OS74%，PFS57%AnnArbor分期是预后主要影响原因，III/IV期患者OS/PFS显著低于I/II期患者GuoHQ,LiuL,WangXF,LinTY,etal.MolClinOncol.Nov;2(6):1172-1176NKT细胞淋巴瘤周剑峰专家讲座第26页同时/序贯化放疗（重点处理I/II期）ConcurrentSequentialBlood.;121(25):4997-5005.NKT细胞淋巴瘤周剑峰专家讲座第27页NCCN指南NKT细胞淋巴瘤周剑峰专家讲座第28页Blood.;121(25):4997-5005.NKT细胞淋巴瘤周剑峰专家讲座第29页NK/T细胞淋巴瘤：现实状况点评早期疾病处理比很好，强调放疗结合化疗(同时或序贯);化疗方案显著改进，许多过去放化疗结论需要重新考虑;晚期NK/T疾病尚无标准方案，需要临床试验及连续改进;NK/T细胞淋巴瘤晚期疾病将会成为关注重点NKT细胞淋巴瘤周剑峰专家讲座第30页血浆EBV-DNA定量评定EBV相关肿瘤最准确指标，与肿瘤负荷、分期、进展正相关BoneMarrowTransplant.;31(2):105-11;Blood.;104(1):243-9NKT细胞淋巴瘤周剑峰专家讲座第31页SMILE方案治疗后血浆EBV-DNA

定量与预后关系预测DFS和OS最有价值独立预后参数Leukemia.;28(4):865-70PersistentlyundetectablePersistentlydetectable<presentationPersistentlydetectable>presentationNKT细胞淋巴瘤周剑峰专家讲座第32页ANKLNKT细胞淋巴瘤周剑峰专家讲座第33页EBV连续感染与基因组不稳定NKT细胞淋巴瘤周剑峰专家讲座第34页ANKL体细胞高频突变NKT细胞淋巴瘤周剑峰专家讲座第35页Themostcommonabnormalities,unbalancedchromosomalabnormalities.NospecificchromosomalabnormalitiesassociatedwithANKLhadbeenidentifiedNKT细胞淋巴瘤周剑峰专家讲座第36页ANKL诊疗关键点ANKL是一个罕见但含有高度侵袭性NK细胞肿瘤急骤起病，病情凶险，生存期仅2周~2个月高度侵袭性经过：不明原因高热、血象三少、肝脾淋巴结肿大、凝血功效异常、噬血细胞综合征、多器官功效衰竭异常NK细胞免疫表型EB病毒DNA阳性IgH/TCR受体基因重排阴性外周血/骨髓找到形态幼稚大颗粒淋巴细胞NKT细胞淋巴瘤周剑峰专家讲座第37页ANKL

PET-CT：25%（阴性）37.5%（特异性）,37.5%（非特异性）NKT细胞淋巴瘤周剑峰专家讲座第38页ANKL流式诊疗关键点CD45异常表达NK细胞表面抗原异常表达NK细胞克隆性异常Ki指数多高于40%TranslRes.;163(6):565-77NKT细胞淋巴瘤周剑峰专家讲座第39页治疗策略1控制HLHVP16+DEX2

减瘤

门冬为基础方案AspaMetDex

3

纠正遗传缺陷SCTNKT细胞淋巴瘤周剑峰专家讲座第40页诊疗策略识别免疫表型异常NK细胞是诊疗关键及时诊疗，纠正初诊时合并噬血细胞综合征非常主要早期使用含L-ASP化疗方案、序贯allo-SCT是当前最可能有效治疗策略。未来治疗策略更新中血浆EBV-DNA是监测肿瘤负荷、评价预后独立参数NKT细胞淋巴瘤周剑峰专家讲座第41页慢性活动性EBV感染（CAEBV）NKT细胞淋巴瘤周剑峰专家讲座第42页CAEBVPostepyHigMedDosw,

;67:481-490NKT细胞淋巴瘤周剑峰专家讲座第43页CAEBV发病进程PatholInt.;58(4):209-17.CAEBVENK/TL&ANKLNKT细胞淋巴瘤周剑峰专家讲座第44页PolymorphicLPD(CategoryA1)PolymorphicLPDwithclonalproliferation(CategoryA2)MonomorphicLPD(CategoryA3)MonomorphicLPDwit