NKT细胞淋巴瘤周剑峰解读

1、NKT细胞淋巴瘤周剑峰解读T 和 NK 细胞肿瘤的分类：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 细

11、胞肿瘤分类的主要变化EBV 相关淋巴增殖性疾病J Korean Med Sci. 2008 Apr;23(2):185-92.EBV 相关 T/NK 细胞增殖性疾病J Dermatol. 2014;41(1):29-39.潜伏性感染，不是裂解式感染，抗病毒治疗无效NK/T 细胞淋巴瘤NK/T 细胞淋巴瘤亚型分布NK/T 细胞淋巴瘤占到所有 PTCL 的10.4%J Clin Oncol, 2008, 26(25):4124-30NK/T 细胞淋巴瘤特征分为鼻型 (68%) 和非鼻型 (26%),其他为侵袭型（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

12、（EBV+，CD56+）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%超过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月鼻型与非鼻型 NK/T 细胞淋巴瘤Nasal type:41%Non-nasal:22%Nasal type:34%Non-nasal:13%Ann Oncol 2008;19:1477-1484放疗在 NK/T 细胞淋巴瘤中的地位仅早期患者可作为根治手段，其余多数与化疗联用什么样的 NK/T 细胞淋巴瘤可以单纯放疗 ？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更新了治疗方案后，化疗是必不可少的治疗手段局限期鼻型NK/T细胞淋巴瘤单纯放疗RR和CR

14、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仍然是必不可少的治疗手段NK/T 细胞肿瘤具有不同寻常的表型特征含门冬酰胺酶的方案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 从第 6 天开始解救，wbc 5000/mlYamag

15、uchi M, et al. JCO, 2011; 29(33):4410-6SMILE 方案疗效及毒性CR率45%, CR+PR 79%1y-OS 55%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近期疗效和毒性近期疗效18 例可评价，14 例获得缓解（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AspaMetDex 方案远期生存中位个月无效患者个月有效后进展患者个月个月晚期结外

17、NK/T细胞淋巴瘤治疗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期化疗后

18、给予IFRT2008-2012 新诊断的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的方案治疗ENKL获得很高的ORR（91%），CR率62%，PR率29%3年 OS 74%，PFS 57%Ann Arbor分期是预后的重要影响因素，III/IV期患者的OS/PFS明显低于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/序贯化放疗（重点解决I/II 期）ConcurrentSequentialBlood. 2013;121(25):4997-5005

20、.NCCN 指南Blood. 2013;121(25):4997-5005.NK/T 细胞淋巴瘤：现状点评早期疾病解决比较好，强调放疗结合化疗 (同步或序贯); 化疗方案明显改进，许多过去的放化疗结论需要重新考虑;晚期 NK/T 疾病尚无标准方案，需要临床试验及持续改进;NK/T 细胞淋巴瘤晚期疾病将会成为关注的重点血浆 EBV-DNA 定量评估EBV相关肿瘤最精确的指标，与肿瘤负荷、分期、进展正相关Bone Marrow Transplant. 2003;31(2):105-11; Blood. 2004;104(1):243-9 SMILE方案治疗后血浆EBV-DNA定量与预后的关系预测D

21、FS和OS最有价值的独立预后参数Leukemia. 2014;28(4):865-70Persistently undetectablePersistently detectablepresentationANKLEBV 持续感染与基因组不稳定ANKL 的体细胞高频突变The most common abnormalities, unbalanced chromosomal abnormalities. No specific chromosomal abnormalities associated with ANKL had been identifiedANKL的诊断要点ANKL是一种罕见

22、但具有高度侵袭性的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、凝血功能异常、噬血细胞综合征、多器官功能衰竭异常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/骨髓找到形态幼稚的大颗粒淋巴细胞ANKL 的 PET-CT：25% （阴性） 37.5%（特异性）, 37.5% （非特异性）ANKL 流式诊断要点Transl Res. 2014;163(6):565-77治疗策略诊疗策略识别免疫表型异常的 NK 细胞是诊断的关键及时诊断，纠正初诊时合并的噬血细胞综合征非常重要早期使用含 L-ASP 的化疗方案、序贯 allo-SCT 是目前最可能有效的治疗策略。未来的治疗策略更新中血浆 EBV-DNA 是监测肿瘤负荷、评价预后的独立参数慢性