NKT细胞淋巴瘤周剑峰解读

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击以编辑母版标题样式,单击以编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击以编辑母版标题样式,单击以编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击以编辑母版标题样式,单击以编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击以编辑母版标题样式,单击以编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击以编辑母版标题样式,单击以编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击以编辑母版标题样式,单击以编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击以编辑母版标题样式,单击以编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击以编辑母版标题样式,单击以编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击以编辑母版标题样式,单击以编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击以编辑母版标题样式,单击以编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击以编辑母版标题样式,单击以编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击以编辑母版标题样式,单击以编辑母版文本样式,第二级,第三级,第四级,第五级,*,NK,细胞增殖性疾病,同济医院血液内科,周剑峰,201,5 年,06,月,07,日,T,和,NK,细胞肿瘤的分类：,WHO 2008,WHO 2008: the mature T-cell and NK-cell neoplasms,T-cell prolymphocytic leukemia,T-cell large granular lymphocytic leukemia,Chronic lymphoproliferative disorder of NK-cells*,Aggressive NK cell leukemia,Systemic EBV+T-cell lymphoproliferative disease of childhood (associated with CAEBV),Hydroa vacciniforme-like lymphoma,Adult T-cell leukemia/lymphoma,Extranodal NK/T cell lymphoma, nasal type,Enteropathy-associatedT-cell lymphoma,Hepatosplenic T-cell lymphoma,Subcutaneous panniculitis-like T-cell lymphoma,Mycosis fungoides,Szary syndrome,Primary cutaneous CD30+T-cell lymphoproliferative disorder,Lymphomatoid papulosis,Primary cutaneous anaplastic large-cell lymphoma,Primary cutaneous aggressive epidermotropic CD8+cytotoxic T-cell lymphoma*,Primary cutaneous gamma-delta T-cell lymphoma,Primary cutaneous small/medium CD4+T-cell lymphoma*,Peripheral T-cell lymphoma, not otherwise specified,Angioimmunoblastic T-cell lymphoma,Anaplastic large cell lymphoma (ALCL), ALK+,Anaplastic large cell lymphoma (ALCL), ALK*,2001 WHO,2008 WHO,Comments,Angioimmunoblastic Lymphoma,Angioimmunoblastic Lymphoma,Definition of origin cell,Anaplastic Large Cell Lymphoma,2 variants based on ALK (+/-) expression,Prognostic importance,Unspecified Peripheral T-cell Lymphoma,Peripheral T-cell Lymphomas not Otherwise Specified,3 variants: lymphoepitelioid lymphoma, T zone lymphoma (2001 WHO) and follicular lymphoma (2008 WHO),T/NK-cell lymphoma, nasal type,T/NK-cell lymphoma, nasal type,No changes,Entheropathy-associated T-cell lymphoma,Entheropathy-associated T-cell lymphomas,Two variants: classical and monomorphic types with genetic changes common to both,Hepatosplenic T-cell lymphoma,Hepatosplenic T-cell lymphoma,No changes,Subcutaneous panniculitis-like T-cell lymphoma,Subcutaneous panniculitis-like T-cell lymphoma,Only ab and associated with autoimmune disorder,Mycosis fungoides,Mycosis fungoides,New staging and new information about pathogenesis,Szary syndrome,Szary syndrome,New markers,Primary cutaneous anaplastic large cell lymphoma,Primary cutaneous anaplastic large cell lymphoma,Recognition of CD8+ cases,Lymphomatoid papulosis,Lymphomatoid papulosis,Three histological types,Primary cutaneous gamma-delta T-cell lymphoma,Three histopathologic patterns: epidermotropic, dermic, and subcutaneous subtypes,Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma,Provisional entity,Primary cutaneous CD4+ small/medium T-cell lymphoma,Provisional entity,Blastic NK-cell lymphoma,Plasmocytoid dendritic cell neoplasm,Now it is one of the myeloid neoplasms,T-cell prolymphocytic leukemia,T-cell prolymphocytic leukemia,No changes,T-cell large granular lymphocytic leukemia,T-cell large granular lymphocytic leukemia,New etiological features and new markers,Chronic lymphoproliferative disorder of NK-cells,Provisional entity,Aggressive NK-cell leukemia,Aggressive NK-cell leukemia,No changes,Adult T-cell leukemia/lymphoma,Adult T-cell leukemia/lymphoma,Definition of the regulatory T-cell normal counterpart,T,和,NK,细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):4124-30,NK/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（,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,5cm,12%,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,OS,19,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,extra-nasal,the,stage,of the disease,Stage I,disease are further stratified based on risk factors,Age 60 years,B symptoms,ECOG performance status 2,Regional lymph node involvement Local tumor invasion,Elevated LDH,High Ki-67 staining,EBV DNA 6.1 x 10,7,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,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,S,teroid (DXM) 40 mg, iv, d2-4,M,TX,2,g/m2, iv, d1,I,FO 1.5g/m2, iv, d2-4,L,-ASP 6000U/m2, iv, d8,10,12,14, 16,18,20,E,topside 100mg/m2, iv ,d2-4,G-CSF,从第,6,天开始解救，,wbc 5000/ml,Yamaguchi M, et al. JCO, 2011; 29(33):4410-6,SMILE,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):4410-6,AspaMetDex,方案,S,teroid,（,DXM,）, 40mg, d1-4, po,M,2, d1, iv drip,I,FO 1.5g/m2, iv, d2-4,L,-Asp 6000U/m,2, d2,4,6,8, im,Etopside 100mg/m2, iv ,d2-4,Jaccard A, et al. Blood, 2011,117:1834-1839.,Smile,方案,S,teroid (DXM) 40 mg, iv, d2-4,M,TX 2 g/m2, iv, d1,I,FO 1.5g/m2, iv, d2-4,L,-ASP 6000U/m2, iv, d8,10,12,14, 16,18,20,E,topside 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,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 lymphoma,G,：,gemcitabine 1g/m2,，,d1,，,D8,O,：,Oxaliplatin 100mg/m2,，,d1,L,：,L-Asparaginase 10,000 U/m2,，,d1-5,D,：,dexamethasone 40mg,，,d1-4,14-day cycle,，,Ann Arbor I/II,期化疗后给予,IFRT,2008-2012,新诊断的,ENKTL,Guo HQ, Liu L, Wang XF, Lin TY, et al.,Mol Clin Oncol. 2014 Nov;2(6):1172-1176,GOLD,方案,Guo HQ, Liu L, Wang XF, Lin TY,et al.,Mol Clin Oncol. 2014 Nov;2(6):1172-1176,GOLD,方案,3Ys PFS 57%,3Ys OS 74%,1 Ys,PFS 87% vs 66%,P 0.001,1 Ys,OS 98% vs 75%,P 0.001,Guo HQ, Liu L, Wang XF, Lin TY,et al.,Mol Clin Oncol. 2014 Nov;2(6):1172-1176,GOLD,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）,Concurrent,Sequential,Blood. 2013;121(25):4997-5005.,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,DFS,和,OS,最有价值的独立预后参数,Leukemia. 2014;28(4):865-70,Persistently undetectable,Persistently detectablepresentation,ANKL,EBV,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 identified,ANKL,的诊断要点,ANKL,是一种罕见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,慢性活动性,EBV,感染（,CAEBV,）,CAEBV,Postepy Hig Med Dosw,2013; 67: 481-490,CAEBV,的发病进程,Pathol Int. 2008;58(4):209-17.,CAEBV,ENK/TL & ANKL,CAEBV,的发病进程,诊断标准,(CAEBV Study Group),Pathol Int. 2008;58(4):209-17.,治疗策略,Bone Marrow Transplant. 2011;46(1):77-83.,异基因造血干细胞移植的疗效,EFS and OS for allo-HSCT,MAC=myeloablative conditioning; RIC=reduced-intensity conditioning.,Bone Marrow Transplant. 2011;46(1):77-83.,发病机制,Highly activated yet ineffective,multisystem inflammatory response/,Immunopathology,噬血细胞性淋巴组织增生症（,HLH,）发病机制,IL-1, IL-6, TNF-,etc.,Tissue Infiltration,（组织浸润）,Cytokine Storm,MSOF,多系统和器官衰竭,IFN-,诊断,(HLH-2004),鉴别诊断,原发性,和,继发性,的鉴别：,分子诊断,继发性,HLH,的,病因诊断,：感染（,EB,病毒感染最常见）、肿瘤、结缔组织病、移植、药物等,治疗,(HLH-2004),NK,细胞肿瘤：关键要点,多数起源于,EBV,慢性感染后转化,疾病累及巨大的人群,诊断治疗存在盲区,具特征性改变，与,B -NHL,是完全不同的疾病,基于疾病机制的新认识，诊断治疗模式正在转化,