NKT細(xì)胞淋巴瘤周劍峰專家講座

NK細(xì)胞增殖性疾病同濟(jì)醫(yī)院血液內(nèi)科周劍峰2015年06月07日NKT細(xì)胞淋巴瘤周劍峰專家講座第1頁(yè)T和NK細(xì)胞腫瘤分類：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細(xì)胞淋巴瘤周劍峰專家講座第2頁(yè)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細(xì)胞腫瘤分類主要改變NKT細(xì)胞淋巴瘤周劍峰專家講座第3頁(yè)EBV相關(guān)淋巴增殖性疾病JKoreanMedSci.Apr;23(2):185-92.NKT細(xì)胞淋巴瘤周劍峰專家講座第4頁(yè)EBV相關(guān)T/NK細(xì)胞增殖性疾病JDermatol.;41(1):29-39.NKT細(xì)胞淋巴瘤周劍峰專家講座第5頁(yè)潛伏性感染，不是裂解式感染，抗病毒治療無(wú)效NKT細(xì)胞淋巴瘤周劍峰專家講座第6頁(yè)NK/T細(xì)胞淋巴瘤NKT細(xì)胞淋巴瘤周劍峰專家講座第7頁(yè)NK/T細(xì)胞淋巴瘤亞型分布NK/T細(xì)胞淋巴瘤占到全部PTCL10.4%JClinOncol,,26(25):4124-30NKT細(xì)胞淋巴瘤周劍峰專家講座第8頁(yè)NKT細(xì)胞淋巴瘤周劍峰專家講座第9頁(yè)NK/T細(xì)胞淋巴瘤特征分為鼻型(68%)和非鼻型(26%),其它為侵襲型（6%）病理表現(xiàn)：形態(tài)多樣，表現(xiàn)為血管中心性、大量壞死和血管浸潤(rùn)表型：大部分為NK細(xì)胞（EBV+，CD56+）NKT細(xì)胞淋巴瘤周劍峰專家講座第10頁(yè)鼻型與非鼻型NK/T細(xì)胞淋巴瘤鼻型非鼻型侵犯部位上呼吸皮膚、睪丸、胃腸道疾病晚期27%68%腫塊>5cm12%68%超出2個(gè)鼻外病灶16%55%LDH升高45%60%B癥狀39%54%5年OS率42%9%中位OS19月4月NKT細(xì)胞淋巴瘤周劍峰專家講座第11頁(yè)鼻型與非鼻型NK/T細(xì)胞淋巴瘤Nasaltype:41%Non-nasal:22%Nasaltype:34%Non-nasal:13%AnnOncol;19:1477-1484NKT細(xì)胞淋巴瘤周劍峰專家講座第12頁(yè)放療在NK/T細(xì)胞淋巴瘤中地位僅早期患者可作為根治伎倆，其余多數(shù)與化療聯(lián)用NKT細(xì)胞淋巴瘤周劍峰專家講座第13頁(yè)什么樣NK/T細(xì)胞淋巴瘤能夠單純放療？Nasal

versusextra-nasalthestageofthediseaseStageIdiseasearefurtherstratifiedbasedonriskfactorsAge≥60years,Bsymptoms,ECOGperformancestatus≥2RegionallymphnodeinvolvementLocaltumorinvasionElevatedLDHHighKi-67stainingEBVDNA≥6.1x107copies/mLNKT細(xì)胞淋巴瘤周劍峰專家講座第14頁(yè)更新了治療方案后，化療是必不可少治療伎倆局限期鼻型NK/T細(xì)胞淋巴瘤單純放療RR和CR分別達(dá)78-94%和66-94%，但5y-OS和中位OS僅分別為35%-83%和50%患者出現(xiàn)皮膚、骨髓、睪丸、內(nèi)臟和淋巴結(jié)侵犯較常見(jiàn)化療依然是必不可少治療伎倆NKT細(xì)胞淋巴瘤周劍峰專家講座第15頁(yè)NK/T細(xì)胞腫瘤含有不一樣尋常表型特征NKT細(xì)胞淋巴瘤周劍峰專家講座第16頁(yè)含門冬酰胺酶方案NKT細(xì)胞淋巴瘤周劍峰專家講座第17頁(yè)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從第6天開(kāi)始解救，wbc>5000/mlYamaguchiM,etal.JCO,;29(33):4410-6NKT細(xì)胞淋巴瘤周劍峰專家講座第18頁(yè)SMILE方案療效及毒性CR率45%,CR+PR79%1y-OS55%毒性反應(yīng)：92%患者出現(xiàn)IV度骨髓抑制，61%出現(xiàn)感染8%出現(xiàn)早期死亡YamaguchiM,etal.JCO,;29(33):4410-6NKT細(xì)胞淋巴瘤周劍峰專家講座第19頁(yè)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細(xì)胞淋巴瘤周劍峰專家講座第20頁(yè)近期療效和毒性近期療效18例可評(píng)價(jià)，14例取得緩解（78%），11例完全緩解（61%）3例治療中死亡14例有效患者，6例在治療結(jié)束后9個(gè)月內(nèi)復(fù)發(fā)NKT細(xì)胞淋巴瘤周劍峰專家講座第21頁(yè)AspaMetDex方案

遠(yuǎn)期生存中位OS12.2個(gè)月無(wú)效患者4.2個(gè)月有效后進(jìn)展患者3.6個(gè)月PFS12.2個(gè)月NKT細(xì)胞淋巴瘤周劍峰專家講座第22頁(yè)晚期結(jié)外NK/T細(xì)胞淋巴瘤治療

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期化療后給予IFRT-新診療ENKTLGuoHQ,LiuL,WangXF,LinTY,etal.MolClinOncol.Nov;2(6):1172-1176NKT細(xì)胞淋巴瘤周劍峰專家講座第23頁(yè)GOLD方案GuoHQ,LiuL,WangXF,LinTY,etal.MolClinOncol.Nov;2(6):1172-1176NKT細(xì)胞淋巴瘤周劍峰專家講座第24頁(yè)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細(xì)胞淋巴瘤周劍峰專家講座第25頁(yè)GOLD方案GOLD方案治療ENKL取得很高ORR（91%），CR率62%，PR率29%3年OS74%，PFS57%AnnArbor分期是預(yù)后主要影響原因，III/IV期患者OS/PFS顯著低于I/II期患者GuoHQ,LiuL,WangXF,LinTY,etal.MolClinOncol.Nov;2(6):1172-1176NKT細(xì)胞淋巴瘤周劍峰專家講座第26頁(yè)同時(shí)/序貫化放療（重點(diǎn)處理I/II期）ConcurrentSequentialBlood.;121(25):4997-5005.NKT細(xì)胞淋巴瘤周劍峰專家講座第27頁(yè)NCCN指南NKT細(xì)胞淋巴瘤周劍峰專家講座第28頁(yè)Blood.;121(25):4997-5005.NKT細(xì)胞淋巴瘤周劍峰專家講座第29頁(yè)NK/T細(xì)胞淋巴瘤：現(xiàn)實(shí)狀況點(diǎn)評(píng)早期疾病處理比很好，強(qiáng)調(diào)放療結(jié)合化療(同時(shí)或序貫);化療方案顯著改進(jìn)，許多過(guò)去放化療結(jié)論需要重新考慮;晚期NK/T疾病尚無(wú)標(biāo)準(zhǔn)方案，需要臨床試驗(yàn)及連續(xù)改進(jìn);NK/T細(xì)胞淋巴瘤晚期疾病將會(huì)成為關(guān)注重點(diǎn)NKT細(xì)胞淋巴瘤周劍峰專家講座第30頁(yè)血漿EBV-DNA定量評(píng)定EBV相關(guān)腫瘤最準(zhǔn)確指標(biāo)，與腫瘤負(fù)荷、分期、進(jìn)展正相關(guān)BoneMarrowTransplant.;31(2):105-11;Blood.;104(1):243-9NKT細(xì)胞淋巴瘤周劍峰專家講座第31頁(yè)SMILE方案治療后血漿EBV-DNA

定量與預(yù)后關(guān)系預(yù)測(cè)DFS和OS最有價(jià)值獨(dú)立預(yù)后參數(shù)Leukemia.;28(4):865-70PersistentlyundetectablePersistentlydetectable<presentationPersistentlydetectable>presentationNKT細(xì)胞淋巴瘤周劍峰專家講座第32頁(yè)ANKLNKT細(xì)胞淋巴瘤周劍峰專家講座第33頁(yè)EBV連續(xù)感染與基因組不穩(wěn)定NKT細(xì)胞淋巴瘤周劍峰專家講座第34頁(yè)ANKL體細(xì)胞高頻突變NKT細(xì)胞淋巴瘤周劍峰專家講座第35頁(yè)Themostcommonabnormalities,unbalancedchromosomalabnormalities.NospecificchromosomalabnormalitiesassociatedwithANKLhadbeenidentifiedNKT細(xì)胞淋巴瘤周劍峰專家講座第36頁(yè)ANKL診療關(guān)鍵點(diǎn)ANKL是一個(gè)罕見(jiàn)但含有高度侵襲性NK細(xì)胞腫瘤急驟起病，病情兇險(xiǎn)，生存期僅2周~2個(gè)月高度侵襲性經(jīng)過(guò)：不明原因高熱、血象三少、肝脾淋巴結(jié)腫大、凝血功效異常、噬血細(xì)胞綜合征、多器官功效衰竭異常NK細(xì)胞免疫表型EB病毒DNA陽(yáng)性IgH/TCR受體基因重排陰性外周血/骨髓找到形態(tài)幼稚大顆粒淋巴細(xì)胞NKT細(xì)胞淋巴瘤周劍峰專家講座第37頁(yè)ANKL

PET-CT：25%（陰性）37.5%（特異性）,37.5%（非特異性）NKT細(xì)胞淋巴瘤周劍峰專家講座第38頁(yè)ANKL流式診療關(guān)鍵點(diǎn)CD45異常表達(dá)NK細(xì)胞表面抗原異常表達(dá)NK細(xì)胞克隆性異常Ki指數(shù)多高于40%TranslRes.;163(6):565-77NKT細(xì)胞淋巴瘤周劍峰專家講座第39頁(yè)治療策略1控制HLHVP16+DEX2

減瘤

門冬為基礎(chǔ)方案AspaMetDex

3

糾正遺傳缺陷SCTNKT細(xì)胞淋巴瘤周劍峰專家講座第40頁(yè)診療策略識(shí)別免疫表型異常NK細(xì)胞是診療關(guān)鍵及時(shí)診療，糾正初診時(shí)合并噬血細(xì)胞綜合征非常主要早期使用含L-ASP化療方案、序貫allo-SCT是當(dāng)前最可能有效治療策略。未來(lái)治療策略更新中血漿EBV-DNA是監(jiān)測(cè)腫瘤負(fù)荷、評(píng)價(jià)預(yù)后獨(dú)立參數(shù)NKT細(xì)胞淋巴瘤周劍峰專家講座第41頁(yè)慢性活動(dòng)性EBV感染（CAEBV）NKT細(xì)胞淋巴瘤周劍峰專家講座第42頁(yè)CAEBVPostepyHigMedDosw,

;67:481-490NKT細(xì)胞淋巴瘤周劍峰專家講座第43頁(yè)CAEBV發(fā)病進(jìn)程PatholInt.;58(4):209-17.CAEBVENK/TL&ANKLNKT細(xì)胞淋巴瘤周劍峰專家講座第44頁(yè)P(yáng)olymorphicLPD(CategoryA1)PolymorphicLPDwithclonalproliferation(CategoryA2)MonomorphicLPD(CategoryA3)MonomorphicLPDwit