NKT細(xì)胞淋巴瘤周劍峰解讀

1、NKT細(xì)胞淋巴瘤周劍峰解讀T 和 NK 細(xì)胞腫瘤的分類：WHO 2008WHO 2008: the mature T-cell and NK-cell neoplasmsT-cell prolymphocytic leukemiaT-cell large granular lymphocytic leukemiaChronic lymphoproliferative disorder of NK-cells*Aggressive NK cell leukemiaSystemic EBV+T-cell lymphoproliferative disease of childhood (assoc

2、iated with CAEBV)Hydroa vacciniforme-like lymphomaAdult T-cell leukemia/lymphomaExtranodal NK/T cell lymphoma, nasal typeEnteropathy-associatedT-cell lymphomaHepatosplenic T-cell lymphomaSubcutaneous panniculitis-like T-cell lymphomaMycosis fungoidesSzary syndromePrimary cutaneous CD30+T-cell lympho

3、proliferative disorderLymphomatoid papulosisPrimary cutaneous anaplastic large-cell lymphomaPrimary cutaneous aggressive epidermotropic CD8+cytotoxic T-cell lymphoma*Primary cutaneous gamma-delta T-cell lymphomaPrimary cutaneous small/medium CD4+T-cell lymphoma*Peripheral T-cell lymphoma, not otherw

4、ise specifiedAngioimmunoblastic T-cell lymphomaAnaplastic large cell lymphoma (ALCL), ALK+Anaplastic large cell lymphoma (ALCL), ALK*2001 WHO2008 WHOCommentsAngioimmunoblastic LymphomaAngioimmunoblastic LymphomaDefinition of origin cellAnaplastic Large Cell Lymphoma 2 variants based on ALK (+/-) exp

5、ressionPrognostic importanceUnspecified Peripheral T-cell Lymphoma Peripheral T-cell Lymphomas not Otherwise Specified3 variants: lymphoepitelioid lymphoma, T zone lymphoma (2001 WHO) and follicular lymphoma (2008 WHO) T/NK-cell lymphoma, nasal typeT/NK-cell lymphoma, nasal typeNo changesEntheropath

6、y-associated T-cell lymphomaEntheropathy-associated T-cell lymphomasTwo variants: classical and monomorphic types with genetic changes common to bothHepatosplenic T-cell lymphomaHepatosplenic T-cell lymphomaNo changesSubcutaneous panniculitis-like T-cell lymphomaSubcutaneous panniculitis-like T-cell

7、 lymphomaOnly ab and associated with autoimmune disorderMycosis fungoidesMycosis fungoidesNew staging and new information about pathogenesis Szary syndromeSzary syndromeNew markersPrimary cutaneous anaplastic large cell lymphomaPrimary cutaneous anaplastic large cell lymphomaRecognition of CD8+ case

8、sLymphomatoid papulosisLymphomatoid papulosisThree histological typesPrimary cutaneous gamma-delta T-cell lymphomaThree histopathologic patterns: epidermotropic, dermic, and subcutaneous subtypesPrimary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphomaProvisional entityPrimary cutan

9、eous CD4+ small/medium T-cell lymphomaProvisional entityBlastic NK-cell lymphomaPlasmocytoid dendritic cell neoplasmNow it is one of the myeloid neoplasmsT-cell prolymphocytic leukemiaT-cell prolymphocytic leukemiaNo changesT-cell large granular lymphocytic leukemiaT-cell large granular lymphocytic

10、leukemiaNew etiological features and new markersChronic lymphoproliferative disorder of NK-cellsProvisional entityAggressive NK-cell leukemiaAggressive NK-cell leukemiaNo changesAdult T-cell leukemia/lymphomaAdult T-cell leukemia/lymphomaDefinition of the regulatory T-cell normal counterpartT 和 NK 細(xì)

11、胞腫瘤分類的主要變化EBV 相關(guān)淋巴增殖性疾病J Korean Med Sci. 2008 Apr;23(2):185-92.EBV 相關(guān) T/NK 細(xì)胞增殖性疾病J Dermatol. 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%J Clin Oncol, 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

12、（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5cm12%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OS19月4月鼻型與非鼻型 NK/T 細(xì)胞淋巴瘤Nasal type:41%Non-nasal:22%Nasal type:34%Non-nasal:13%Ann Oncol 2008;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 versus ex

13、tra-nasalthe stage of the diseaseStage I disease are further stratified based on risk factors Age 60 years,B symptoms, ECOG performance status 2Regional lymph node involvement Local tumor invasion Elevated LDHHigh Ki-67 staining EBV DNA 6.1 x 107 copies/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

14、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) 40 mg, iv, d2-4MTX 2 g/m2, iv, d1IFO 1.5g/m2, iv, d2-4L-ASP 6000U/m2, iv, d8,10,12,14, 16,18,20Etopside 100mg/m2, iv ,d2-4G-CSF 從第 6 天開(kāi)始解救，wbc 5000/mlYamag

15、uchi M, et al. JCO, 2011; 29(33):4410-6SMILE 方案療效及毒性CR率45%, CR+PR 79%1y-OS 55%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Yamaguchi M, et al. JCO, 2011; 29(33):4410-6AspaMetDex 方案Steroid （DXM）, 40mg, d1-4, poM2, d1, iv dripIFO 1.5g/m2, iv, d2-4L-Asp 6000U/m2, d2,4,6,8, imEtopside 100mg/m2, iv ,d2-4Jaccard A,

16、 et al. Blood, 2011,117:1834-1839. Smile方案Steroid (DXM) 40 mg, iv, d2-4MTX 2 g/m2, iv, d1IFO 1.5g/m2, iv, d2-4L-ASP 6000U/m2, iv, d8,10,12,14, 16,18,20Etopside 100mg/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)期生存中位個(gè)月無(wú)效患者個(gè)月有效后進(jìn)展患者個(gè)月個(gè)月晚期結(jié)外

17、NK/T細(xì)胞淋巴瘤治療GOLD方案Efficacy of gemcitabine combined with oxaliplatin, Lasparaginase and dexamethasone in patients with newlydiagnosed extranodal NK/Tcell lymphomaG：gemcitabine 1g/m2，d1， D8O：Oxaliplatin 100mg/m2，d1L：L-Asparaginase 10,000 U/m2，d1-5D：dexamethasone 40mg，d1-414-day cycle，Ann Arbor I/II期化療后

18、給予IFRT2008-2012 新診斷的ENKTLGuo HQ, Liu L, Wang XF, Lin TY, et al. Mol Clin Oncol. 2014 Nov;2(6):1172-1176GOLD方案Guo HQ, Liu L, Wang XF, Lin TY,et al. Mol Clin Oncol. 2014 Nov;2(6):1172-1176GOLD方案3Ys PFS 57%3Ys OS 74%1 Ys PFS 87% vs 66%P 0.0011 Ys OS 98% vs 75%P 0.001Guo HQ, Liu L, Wang XF, Lin TY,et al

19、. Mol Clin Oncol. 2014 Nov;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 OS 74%，PFS 57%Ann Arbor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Guo HQ, Liu L, Wang XF, Lin TY,et al. Mol Clin Oncol. 2014 Nov;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

20、.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)Bone Marrow Transplant. 2003;31(2):105-11; Blood. 2004;104(1):243-9 SMILE方案治療后血漿EBV-DNA定量與預(yù)后的關(guān)系預(yù)測(cè)D

21、FS和OS最有價(jià)值的獨(dú)立預(yù)后參數(shù)Leukemia. 2014;28(4):865-70Persistently undetectablePersistently detectablepresentationANKLEBV 持續(xù)感染與基因組不穩(wěn)定ANKL 的體細(xì)胞高頻突變The most common abnormalities, unbalanced chromosomal abnormalities. No specific chromosomal abnormalities associated with ANKL had been identifiedANKL的診斷要點(diǎn)ANKL是一種罕見(jiàn)

22、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)Transl Res. 2014;163(6):565-77治療策略診療策略識(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