NKT細(xì)胞淋巴瘤周劍峰解讀

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

T和NK細(xì)胞腫瘤的分類：WHO2008WHO2008:thematureT-cellandNK-cellneoplasmsT-cellprolymphocyticleukemiaT-celllargegranularlymphocyticleukemiaChroniclymphoproliferativedisorderofNK-cells*AggressiveNKcellleukemiaSystemicEBV+T-celllymphoproliferativediseaseofchildhood(associatedwithCAEBV)Hydroavacciniforme-likelymphomaAdultT-cellleukemia/lymphomaExtranodalNK/Tcelllymphoma,nasaltypeEnteropathy-associatedT-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?*

2001WHO2008WHOCommentsAngioimmunoblasticLymphomaAngioimmunoblasticLymphomaDefinitionoforigincellAnaplasticLargeCellLymphoma2variantsbasedonALK(+/-)expressionPrognosticimportanceUnspecifiedPeripheralT-cellLymphomaPeripheralT-cellLymphomasnotOtherwiseSpecified3variants:lymphoepitelioidlymphoma,Tzonelymphoma(2001WHO)andfollicularlymphoma(2008WHO)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)胞腫瘤分類的主要變化

EBV相關(guān)淋巴增殖性疾病

JKoreanMedSci.2008Apr;23(2):185-92.EBV相關(guān)T/NK細(xì)胞增殖性疾病

JDermatol.2014;41(1):29-39.潛伏性感染，不是裂解式感染，抗病毒治療無(wú)效

NK/T細(xì)胞淋巴瘤

NK/T細(xì)胞淋巴瘤亞型分布

NK/T細(xì)胞淋巴瘤占到所有PTCL的10.4%JClinOncol,2008,26(25):4124-30NK/T細(xì)胞淋巴瘤特征

?分為鼻型(68%)和非鼻型(26%),其他為侵襲型（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+）

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>5cm

12%

68%

超過(guò)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OS

19月

4月

鼻型與非鼻型NK/T細(xì)胞淋巴瘤

Nasaltype:41%Non-nasal:22%Nasaltype:34%Non-nasal:13%AnnOncol2008;19:1477-1484放療在NK/T細(xì)胞淋巴瘤中的地位

僅早期患者可作為根治手段，其余多數(shù)與化療聯(lián)用

什么樣的NK/T細(xì)胞淋巴瘤可以單純放療

？

Nasal

versusextra-nasal

thestageofthedisease

StageIdiseasearefurtherstratifiedbasedonriskfactors

Age≥60years,

Bsymptoms,ECOGperformancestatus≥2

RegionallymphnodeinvolvementLocaltumorinvasionElevatedLDHHighKi-67stainingEBVDNA≥6.1x107copies/mL更新了治療方案后，化療是必不可少的治療手段

?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)

?化療仍然是必不可少的治療手段

NK/T細(xì)胞腫瘤具有不同尋常的表型特征

含門(mén)冬酰胺酶的方案

SMILE方案

?Smile方案

–Steroid(DXM)40mg,iv,d2-4–MTX2g/m2,iv,d1–IFO1.5g/m2,iv,d2-4–L-ASP6000U/m2,iv,d8,10,12,14,16,18,20–Etopside100mg/m2,iv,d2-4?G-CSF從第6天開(kāi)始解救，wbc>5000/mlYamaguchiM,etal.JCO,2011;29(33):4410-6SMILE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,2011;29(33):4410-6AspaMetDex方案

?Steroid（DXM）,40mg,d1-4,po?MTX3.0g/m2,d1,ivdrip?IFO1.5g/m2,iv,d2-4?L-Asp6000U/m2,d2,4,6,8,im?Etopside100mg/m2,iv,d2-4

JaccardA,etal.Blood,2011,117:1834-1839.

?Smile方案

–Steroid(DXM)40mg,iv,d2-4–MTX2g/m2,iv,d1–IFO1.5g/m2,iv,d2-4–L-ASP6000U/m2,iv,d8,10,12,14,16,18,20–Etopside100mg/m2,iv,d2-4近期療效和毒性

?近期療效

–18例可評(píng)價(jià)，14例獲得緩解（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)

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

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IFRT2008-2012新診斷的ENKTLGuoHQ,LiuL,WangXF,LinTY,etal.MolClinOncol.2014Nov;2(6):1172-1176GOLD方案

GuoHQ,LiuL,WangXF,LinTY,etal.MolClinOncol.2014Nov;2(6):1172-1176GOLD方案

3YsPFS57%3YsOS74%1YsPFS87%vs66%P<0.0011YsOS98%vs75%P<0.001GuoHQ,LiuL,WangXF,LinTY,etal.MolClinOncol.2014Nov;2(6):1172-1176GOLD方案

?GOLD的方案治療ENKL獲得很高的ORR（91%），CR率62%，PR率29%?3年OS74%，PFS57%?AnnArbor分期是預(yù)后的重要影響因素，III/IV期患者的OS/PFS明顯低于I/II期患者

GuoHQ,LiuL,WangXF,LinTY,etal.MolClinOncol.2014Nov;2(6):1172-1176同步/序貫化放療（重點(diǎn)解決I/II期）

ConcurrentSequentialBlood.2013;121(25):4997-5005.NCCN指南

Blood.2013;121(25):4997-5005.NK/T細(xì)胞淋巴瘤：現(xiàn)狀點(diǎn)評(píng)

?早期疾病解決比較好，強(qiáng)調(diào)放療結(jié)合化療(同步或序貫);?化療方案明顯改進(jìn)，許多過(guò)去的放化療結(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)及持續(xù)改進(jìn);?NK/T細(xì)胞淋巴瘤晚期疾病將會(huì)成為關(guān)注的重點(diǎn)

血漿EBV-DNA定量

?評(píng)估EBV相關(guān)腫瘤最精確的指標(biāo)，與腫瘤負(fù)荷、分期、進(jìn)展正相關(guān)

BoneMarrowTransplant.2003;31(2):105-11;Blood.2004;104(1):243-9SMILE方案治療后血漿EBV-DNA定量與預(yù)后的關(guān)系

?預(yù)測(cè)DFS和OS最有價(jià)值的獨(dú)立預(yù)后參數(shù)

Leukemia.2014;28(4):865-70Persistentlyundetectable

Persistentlydetectable<presentation

Persistentlydetectable>presentation

ANKL

GeneNameChrom:PositionMutionTypePredictionfromSIFTPredictionfromPolyphen-2SubstitutionGenedescriptionThecandidatesomaticvariantsinFHL2patient

FASTKD3chr5:7868314SpliceSite---FASTkinasedomains3HOXA10chr7:27213757cds-Indel----SVEP1chr9:113137745SpliceSite---vonWillebrandfactortypeA,EGFandpentraxindomaincontaining1ThecandidatevariantsrelatedwiththefamilyunderanautosomalrecessivemodelPCDH18chr4:138442574missenceTOLERATEDprobablydamagingS1006Lprotocadherin18CDK11Bchr1:1654067missence----MAGEC1chrX:140993945missenceTOLERATEDbenignF252SmelanomaantigenfamilyC,1NOS1chr12:117691485missenceTOLERATEDbenignL869Pnitricoxidesynthase1(neuronal)PPP1R14BP3chr4:140036422missence---proteinphosphatase1,regulatory(inhibitor)subunit14Bpseudogene3ThecandidatevariantsrelatedwiththefamilyunderanautosomaldominantmodelMLL3chr7:151970859missenseDAMAGINGprobablydamagingG315Smyeloid/lymphoidormixed-lineageleukemia3PCDH18chr4:138442574missenceTOLERATEDprobablydamagingS1006Lprotocadherin18ANKRD36chr2:97830177missenceTOLERATED-G501V-EBV持續(xù)感染與基因組不穩(wěn)定

ANKL的體細(xì)胞高頻突變

Themostcommonabnormalities,unbalancedchromosomalabnormalities.NospecificchromosomalabnormalitiesassociatedwithANKLhadbeenidentifiedANKL的診斷要點(diǎn)

ANKL是一種罕見(jiàn)但具有高度侵襲性的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、凝血功能異常、噬血細(xì)胞綜合征、多器官功能衰竭

?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)幼稚的大顆粒淋巴細(xì)胞

ANKL的PET-CT：25%（陰性）37.5%（特異性）,37.5%（非特異性）

ANKL流式診斷要點(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.2014;163(6):565-77治療策略

1?控制HLH?VP16+DEX2?

減瘤

?

門(mén)冬為基礎(chǔ)方案AspaMetDex3?

糾正遺傳缺陷

?SCT診療策略

?識(shí)別免疫表型異常的NK細(xì)胞是診斷的關(guān)鍵

?及時(shí)診斷，糾正初診時(shí)合并的噬血細(xì)胞綜合征非常重要

?早期使用含L-ASP的化療方案、序貫allo-SCT是目前最可能有效的治療策略。未來(lái)的治療策略更新中

?血漿EBV-DNA是監(jiān)測(cè)腫瘤負(fù)荷、評(píng)價(jià)預(yù)后的獨(dú)立參數(shù)

慢性活動(dòng)性EBV感染（CAEBV）CAEBV

PostepyHigMedDosw,2013;67:481-490

CAEBV的發(fā)病進(jìn)程

PatholInt.2008;58(4):209-17.

CAEBV

ENK/TL&ANKLPolymorphicLPD(Cate