Management of Advanced and Relapsed/Refractory Extranodal Natural Killer T-Cell Lymphoma: An Analysis of Stem Cell Transplantation and Chemotherapy Outcomes

Background

Extra-Nodal natural killer/T-cell lymphoma (ENKL) is a rare lymphoma representing approximately 5-10% of T-cell non-Hodgkin lymphomas diagnosed in the United States each year. Patients with advanced stage III/IV ENKL and relapsed refractory ENKL have a poor prognosis even despite aggressive therapy and stem cell transplantation (SCT). We conducted a review of the management of 37 patients with advanced-stage and relapsed/refractory ENKL in a predominantly non-Asian cohort evaluating both chemotherapy and SCT outcomes.

Intracranial Nasal Natural Killer/T-cell Lymphoma: Immunopathologically-Confirmed Case and Review of Literature

Summary Advances in immunophenotypic profiling now permit characterization of natural killer/T-cell (NK/T-cell) lymphoma as distinct from other extranodal T- and B-cell Non-Hodgkin’s lymphomas. NK/T-cell lymphoma presents most commonly in the nasal cavity. Disease progression to the central nervous system (CNS) is a rare phenomenon. We present here, to our knowledge, the first immunophenotypically-confirmed case of direct extension of nasal NK/T-cell lymphoma to the brain. In addition, we review the literature with respect to NK/T-cell lymphoma metastasis to the CNS. The overall prevalence of NK/T-cell lymphoma CNS metastasis is less than 3%. Although rare, CNS invasion portends a poor prognosis, emphasizing the importance of early and accurate immunophenotype profiling and the need for novel, aggressive therapy.     

Icaritin induces lytic cytotoxicity in extranodal NK/T-cell lymphoma

Background

Extranodal NK/T-cell lymphoma (ENKL) is an aggressive hematological malignancy associated with Epstein–Barr virus (EBV) infection. It is often resistant to conventional chemotherapy and has a poor prognosis. Icaritin, a compound derived from Chinese herbal medicine, Herba Epimedii, has been reported to exert antitumor effects on a variety of cancer cell lines. In the present study, we investigated the cytotoxic effects of Icaritin on the two EBV-positive ENKL cell lines SNK-10 and SNT-8, along with the underlying molecular mechanisms.

Methods

ENKL cell lines SNK-10 and SNT-8 were exposed to different concentrations of Icaritin for the indicated time. Treated cells were analyzed for cell proliferation, cell cycle, and cell apoptosis. Phosphorylation of Stat3 and Akt proteins in signaling pathways and the EBV-encoded LMP1 proteins were measured by Western blot. Expression of EBV genes was assessed by Real-Time PCR.

Results

Our results showed that Icaritin dose-dependently inhibits ENKL cell proliferation and induces apoptosis and cell cycle arrest at G₂/M phase. Additionally, Icaritin upregulates Bax, downregulates Bcl-2 and pBad, and activates caspase-3 and caspase-9. The anti-proliferative and pro-apoptotic effects of Icaritin are likely mediated by inhibition of Stat3 and Akt pathways through LMP1 downregulation. Importantly, Icaritin induces EBV lytic gene expression in ENKL cells, and the combination of Icaritin and the antiviral drug ganciclovir (GCV) is more effective in inducing ENKL cells apoptosis than Icaritin or GCV alone.

Conclusions

These findings indicate that EBV-targeted approaches may have significant therapeutic potential for ENKL treatment.     

EB病毒感染与早期鼻型结外NK/T细胞淋巴瘤患者疗效及预后的关系

目的 探讨早期结外鼻型NK/T细胞淋巴瘤（ENKTCL）患者治疗前EBV DNA载量、治疗前血清EA-IgA及VCA-IgA抗体水平与临床特征、治疗反应及预后的关系。方法 分析78例早期结外鼻型NK/T细胞淋巴瘤患者的临床特征及影响预后的因素。结果 治疗前EBV DNA、VCA-IgA、EA-IgA阳性率分别为43.6%、20.5%、14.1%。EBV DNA与Ann Arbor分期、原发部位、PTI、治疗后未获得CR显著相关（均P<0.05）。VCA-IgA、EA-IgA滴度分别与EBV DNA、治疗后未获得CR显著相关（均P<0.05）。多因素分析发现年龄、EBV DNA、治疗后未获得CR为早期ENKTCL患者OS的独立预后因素（均P<0.05）;年龄、EBV DNA、原发鼻腔外上呼吸消化道、治疗后未获得CR（均P<0.05）则为早期ENKTCL患者PFS的独立预后因素。结论 治疗前EBV DNA阳性与较晚的Ann Arbor分期、PTI、原发鼻腔外上呼吸消化道、治疗反应差有关。EA-IgA、VCA-IgA水平升高与EBVDNA阳性、治疗反应差有关。治疗前EBV DNA可用于ENKTCL的风险分层及预后预测,而EA-IgA、VCA-IgA对于ENKTCL的预后指导作用有限。     

P-GEMOX方案与CHOP方案一线治疗结外NK/T淋巴瘤的疗效对比

目的:比较含培门冬酶方案P-GEMOX与传统CHOP方案一线治疗结外NK/T淋巴瘤的近期疗效、远期生存及安全性,并探讨其预后影响因素.方法:回顾性分析我院2010 ～2015年45例结外NK/T淋巴瘤患者的临床资料,比较两种治疗方案之间的疗效,并进行预后因素分析.结果:28例早期结外NK/T淋巴瘤患者治疗以放化疗联合为主,ORR为85.7％(24/28),CR为82.1％,其中CHOP方案联合放疗组ORR为80.0％(12/15),CR为73.3％,2年OS率为73.3％,PFS率为66.7％.P-GEMOX方案联合放疗组ORR为92.3％(12/13),CR为92.3％,2年OS率为92.3％,PFS率为92.3％,两组的ORR,OS及PFS率差异无统计学意义(P＞0.05).17例晚期患者治疗以化疗为主,ORR 41.1％ (7/17),CR为17.6％,其中CHOP方案治疗组ORR为12.5％(1/8),CR为0％,1年OS率为12.5％,PFS率为0％,P-GEMOX方案治疗组ORR为66.7％ (6/9),CR为33.3％,1年OS率为55.6％,PFS率为11.1％,两组的ORR、OS、PFS率差异均有统计学意义(P＜0.05).单因素分析提示:低ECOG评分(0～1)、分期早、不合并B症状、血清LDH正常、低NKIPI评分(0～1)、EB病毒编码的小RNA(the EBV enco-ded small RNA,EBER)阴性患者有更长生存期,差异有统计学意义(P＜0.001).多因素分析提示:分期是影响患者预后的唯一因素,差异有统计学意义(P＜0.05).结论:早期患者采用P-GEMOX方案与CHOP方案化疗的疗效相当,晚期患者采用P-GEMOX方案化疗较CHOP方案可明显提高疗效且改善预后.临床分期是影响结外NK/T淋巴瘤预后的独立因素.     

Ⅱ期上呼吸消化道结外鼻型NK/T细胞淋巴瘤患者受累区域淋巴结水平的预后价值

目的 分析区域淋巴结转移范围在Ⅱ期上呼吸消化道结外鼻型NK/T细胞淋巴瘤(UADT-NKTCL)患者中的预后价值。方法 回顾分析1987—2013年间本院初治的97例Ⅱ期UADT-NKTCL患者资料,分析淋巴结转移范围与预后关系。全组患者52例原发鼻腔,45例原发鼻腔外上呼吸消化道。多数患者接受以放疗为主治疗,65例接受放化疗,27例单纯放疗,5例单纯化疗。Kaplan-Meier法计算生存率,Logrank法检验和单因素预后分析,Cox模型多因素分析。结果 全组患者5年OS、PFS分别为57%、49%。单因素和多因素分析都显示伴有下颈(环状软骨下缘水平以下)淋巴结转移的患者预后更差,其中位生存时间仅19.3个月,2、5年OS分别为28%、11%,而未伴有下颈淋巴结受累的Ⅱ期患者5年OS达68%(P=0.000)。治疗模式明显影响预后,综合治疗患者5年OS、PFS分别为64%、52%,显著优于单纯放疗或化疗患者的40%(P=0.006)和42%(P=0.088)。结论 区域淋巴结受累水平是Ⅱ期UADT-NKTCL的独立预后因素,伴有下颈淋巴结受累患者预后很差。     

Natural Killer/T-cell Neoplasms: Analysis of Incidence,Patient Characteristics,and Survival Outcomes in the United States

Background

Limited data are available regarding the incidence, survival patterns, and long-term outcomes of natural killer (NK)/T-cell neoplasms in the United States.

P-Gemox方案联合调强放疗治疗早期结外NK/T细胞淋巴瘤的临床疗效

目的 探讨P-Gemox方案联合调强放疗治疗早期结外NK/T细胞淋巴瘤（extranodal NK/T-cell lymphoma,ENKTL）的疗效。方法 回顾性分析四川省肿瘤医院2012年3月至2017年10月初治的73例ENKTL患者的临床资料,根据治疗方案分为P-Gemox方案夹心放疗组（n=38）和P-Gemox方案序贯放疗组（n=35）,比较两组患者的近期和远期临床疗效。结果 73例ENKTL患者总有效率（ORR）为95.9%,3年无进展生存率（PFS）为73.5%,3年总生存率（OS）为81.9%。P-Gemox方案夹心放疗组ORR为97.4%,3年PFS和OS分别为74.2%和84.1%。P-Gemox方案序贯放疗组ORR为94.3%,3年PFS和OS分别为72.6%和79.2%。两组ORR、PFS和OS差异均无统计学意义（P＞0.05）。控制相关潜在混杂因素后,多因素Cox回归分析显示,P-Gemox方案夹心放疗组与P-Gemox方案序贯放疗组的PFS相当（HR=0.617,95%CI：0.353~1.081,P=0.091）,而P-Gemox方案夹心放疗组较P-Gemox方案序贯放疗组OS更好 （HR=0.556,95%CI：0.314~0.982,P=0.043）。两组化疗毒副反应以Ⅰ～Ⅱ级为主,其中P-Gemox方案夹心放疗组较P-Gemox方案序贯放疗组更容易发生Ⅰ～Ⅱ度转氨酶升高（P＜0.05）,血液学、胃肠道等毒副反应,发生率差异无统计学意义（P＞0.05）。结论 P-Gemox方案夹心放疗与P-Gemox方案序贯放疗的近期疗效和PFS相当,但P-Gemox方案夹心放疗较P-Gemox方案序贯放疗可提高患者OS。     

鼻和鼻型NK/T细胞淋巴瘤的治疗进展

鼻和鼻型NK/T细胞淋巴瘤是一种起源于NK细胞的少见的非霍奇金淋巴瘤,其临床病理表现独特,肿瘤浸润以血管为中心,伴有血管破坏和灶性坏死。其几乎可以侵及所有结外器官,侵袭性高,极易产生耐药性而疗效差,预后差,生存时间短,目前尚无最佳的治疗模式。本文对近年来采用的放疗,传统化疗,大剂量化疗结合干细胞移植和基于左旋门冬酰胺酶的联合化疗等治疗模式进行综合论述,比较各疗法的优缺点并介绍了最新发展趋势。     

NK/T细胞淋巴瘤相关基因异常的研究进展

NK/T细胞淋巴瘤(NK/T-cell lymphoma,NKTCL)的发病与EB病毒(epstein-barr virus,EBV)感染、基因异常、染色体异常、信号通路及蛋白表达异常相关.本文就NKTCL相关基因异常的研究进展做一简要综述.NKTCL基因异常包括基因突变和缺失等,可影响细胞增殖、分化、凋亡及信号转导.其中,EBV相关基因LMP1表达产物为LMP1蛋白(latent membrane protein 1),破坏细胞信号传导通路;KIR2DI4、EZH2、DDX3X及c-Myc基因异常通过调节免疫应答、DNA转录等途径影响细胞周期;TP53、JAK3、PTPRK、PRDM1及BCOR基因异常通过编码蛋白、影响细胞内信号转导通路等途径抑制细胞凋亡,进而导致细胞的恶性转化.在基因水平对NKTCL进行深入研究会帮助我们进一步认识NKTCL的发病机制,为疾病的治疗提供新的思路与靶点,完善预后评价体系.     

Primary Testicular NK/T-Cell Lymphoma：A Study of Two Cases and Review of Literature

Primary testicular NK/T-cell lymphoma is an extremely rare entity progressed rapidly. The aim of this study was to examine clinical and pathological features of primary testicular NK/T-cell lymphoma and to investigate the effective diagnosis and prognosis. In this paper, the two cases of primary testicular NK/T-cell lymphoma were observed by light microscopy, immunohistochemistry and examined by in situ hybridization for Epstein-Barr Virus (EBV) DNA and the literatures were reviewed. The two patients respectively present with bilateral and right-side painless testicular enlargement. The morphology of neoplastic cells of case 1 were small to medium, tumor cells of case 2 were small, medium and large mixed. The tumor cells grew diffusely with irregular and distort nuclear, destructed the organizational structure of the normal testis, and damaged blood vessels, meanwhile, coagulation necrosis was exist. Immunohistochemical staining of neoplastic cells showed positive for CD45, CD2, CD56, CD3ɛ (cytoplasm staining pattern), CD45RO and Granzyme B, and negative for CD57, CD20, CD79α, CD30, CK, MPO, TdT, Bcl-2 and PLAP were negative. In addition, the EBV DNA was detected in the lymphoma by In situ hybridization. In conclusion, the expression of CD56, CD3ɛ, and Granzyme B associated proteins and EBV examination by in situ hybridization play a vital role in diagnosis and differential diagnosis of primary testicular NK/T-cell lymphoma.     

结外鼻型NK/T细胞淋巴瘤30例诊疗分析

目的 探讨结外鼻型NK/T细胞淋巴瘤的临床特征及预后影响因素.方法 对按照WHO淋巴瘤分类标准,经病理确诊的30例结外鼻型NK／T细胞淋巴瘤患者临床特点、长期生存率、预后因素进行分析.结果 30例结外鼻型NK/T细胞淋巴瘤患者,以男性患者居多,中位发病年龄45岁,年轻患者鼻外型较多见,且更易合并噬血细胞综合征.实验室检查发现白细胞、血红蛋白、血小板、丙氨酸氨基转移酶、乳酸脱氢酶、清蛋白常有异常,且在生存组与死亡组之间,血红蛋白下降、血清清蛋白下降程度的差异有统计学意义.死亡患者发病年龄相对较轻,鼻外型多见,更多伴B症状、噬血细胞综合征,国际预后指数（IPI）评分较高,骨髓累及发生率较高,临床分期更晚,实验室检查异常更多.Kaplan-Meier单因素分析显示发病年龄、是否鼻腔来源、有无B症状、有无骨髓累及、是否伴发噬血细胞综合征、IPI评分、临床分期、治疗方法,以及有无白细胞、血红蛋白、血小板、血清乳酸脱氢酶、清蛋白水平异常,有无肝功能损伤等因素,均可影响预后;采用Cox回归模型进行多因素预后分析,显示有无血清LDH升高及有无骨髓累及为影响预后的独立危险因素.结论 结外鼻型NK/T细胞淋巴瘤多见于中年男性,侵袭性高,病初临床表现多样.相比鼻腔NK/T细胞淋巴瘤患者,鼻外型患者发病年龄更轻,实验室异常更明显,更易伴发噬血细胞综合征,更易累及骨髓,预后更差.有无血清LDH升高及有无骨髓累及为影响预后的独立危险因素.     

Prognostic Nomogram for Overall Survival in Early Stage Extranodal Natural Killer/T Cell Lymphoma Treated With High-Dose Radiotherapy

BackgroundThe aim of this study was to develop a prognostic nomogram for early stage extranodal natural killer/T-cell lymphoma, nasal type (ENKL) treated with high-dose radiotherapy (RT).Patients and MethodsA total of 81 patients at 2 cancer centers with stage I to IIE ENKL who received chemotherapy (CT) and high-dose RT were retrospectively analyzed. The development of the nomogram was on the basis of the Cox proportional hazards model. We implemented the concordance index (C-index) and performed a calibration curve to determine its predictive and discriminatory capacity and compared our nomogram with the International Prognostic Index (IPI) and the Korean Prognostic Index (KPI).ResultsThe nomogram included 4 important variables and used a multivariate analysis: lactate dehydrogenase, primary tumor invasion, tumor response, and CT regimen. The 5-year OS rate and progression-free survival were 64.7% and 57.5%, respectively for the entire group. The C-index of the nomogram for overall survival (OS) prediction was 0.87, and it was superior to the predictive power of the IPI and KPI. The calibration curve showed that the nomogram accurately predicted the 5-year OS.ConclusionThe proposed nomogram could provide an individualized risk estimate of the OS for early stage ENKL treated with CT and high-dose RT.     

结外NK/T细胞淋巴瘤患者鼻腔菌群失调与预后的关系

目的 探讨鼻腔菌群失调与结外NK/T细胞淋巴瘤（extranodal NK/T-cell lymphoma,ENKTCL）预后的相关性。方法 回顾性分析244例初治ENKTCL患者的临床资料及鼻拭子培养结果,根据是否存在鼻腔菌群失调将患者分为菌群正常组（n=114）和菌群失调组（n=130）,并分析菌群失调与患者临床病理特征、治疗效果及预后的关系。结果  菌群失调组患者共培养出409株优势菌株,以金黄色葡萄球菌、草绿色链球菌、表皮葡萄球菌及铜绿假单胞菌为主。菌群失调组患者的乳酸脱氢酶升高比例高于菌群正常组（P=0.044）,预后评分PINK≥1的中危或高危患者比例亦高于菌群正常组（P=0.003）。治疗结束时,菌群失调组患者的完全缓解率显著低于菌群正常组（45.5% vs 61.4%,P<0.05）,5年无疾病进展生存率亦低于菌群正常组（48.4% vs 63.9%,P=0.048）。亚组分析显示,早期及PINK低危患者中,菌群失调与否与患者的无疾病进展生存期有关（P=0.022, 0.011）。结论 鼻腔菌群失调与ENKTCL患者预后密切相关,针对鼻腔菌群失调的措施可能进一步改善ENKTCL的治疗效果及预后。     

107例鼻型NK/T细胞淋巴瘤临床特点和预后分析

目的分析107例鼻型NK/T细胞淋巴瘤的临床特点,探讨影响预后的因素。方法回顾性分析2002年1月-2010年12月间福建省肿瘤医院收治的107例完整资料的鼻型NK/T细胞淋巴瘤患者,将临床特点及实验室检查结果进行单因素分析,单因素分析有统计学意义的指标纳入多因素分析。结果107例患者男女比例为2.2∶1(74[DK]∶33),年龄9～83岁,中位年龄42岁。原发部位：鼻腔75例（70％）、韦氏环24例（22％）、其他部位8例;伴颈部淋巴结受侵12例（11％）、骨髓侵犯2例;82％为Ann Arbor分期Ⅰ/Ⅱ期; 83%国际预后指数评分为0～1分, 52％伴有B症状。单纯化疗26例、单纯放疗26例、化放疗综合治疗55例。 初治完全缓解率61％,5年生存率47.2%,多因素分析显示年龄、分期、近期疗效是NK/T细胞淋巴瘤的独立预后因素。结论鼻型NK/T细胞淋巴瘤主要侵犯鼻腔和韦氏环,男性多见,常伴B症状,放化疗为其主要治疗手段,年龄、分期、近期疗效可作为预后参考因素。