淋巴瘤相关的噬血细胞淋巴组织细胞增生症的临床研究

发布时间：2018-05-08 23:19

本文选题：噬血细胞淋巴组织细胞增生症 + 血液系统肿瘤　；参考：《南京医科大学》2017年博士论文

【摘要】：第一部分成人噬血细胞淋巴组织细胞增生症目的成人噬血细胞淋巴组织细胞增生症(AHLH)大部分为继发性,少部分为迟发型FHLH。AHLH的临床症状多种多样,但是无特异性,一般表现为高热、肝脾肿大、全血细胞减少、凝血功能异常、高甘油三酯血症、高细胞因子血症、高铁蛋白血症,高乳酸脱氢酶血症及多器官功能衰竭等。目前为止尚未发现能够预测其早期死亡的明确的参数。本文通过收集我院327例成人HLH的临床资料并进行分析,探讨其临床特征、治疗及识别与早期死亡相关的危险因素,加强临床医生对成人HLH的认识。方法收集患者的详细临床病例资料、实验室检查结果,以电话形式对患者进行随访,随访截止时间为2016-03-31。327例患者中,8例患者失访,随访率97.6%。死亡日期作为研究截止日期,失访或截止随访患者仍存活归类为删失(也称截尾或终检)。采用回顾性分析方法,计数资料以比例或百分比表示,采用Cox回归模型对相关因素进行单因素分析,筛选出有统计学意义的因素行多因素分析,生存曲线由Kaplan-Meier法绘制并估计中位生存时间,组间生存率比较采用Log-Rank检验法,P0.05被认为有统计学意义。结果入组的327例患者中位年龄为53岁(18～93岁)。其中男181例,女146例。大多数患者起病时表现为发热、肝、脾及淋巴结肿大和骨髓标本中血细胞吞噬。133例(42%)患者在诊断后8周内死亡。继发性因素包括感染(n= 129;39%)、血液系统肿瘤(n=107;33%)、不明原因(n = 68;21%)和自身免疫性疾病(n = 21;7%)。本研究随访发现与早期死亡风险因素包括(1)EBV-DNA阳性(HR3.594,95%CI;[1.443,8.952];P=0.001)、(2)低蛋白血症(HR 1.10[1.01,1.20];P = 0.046)和(3)正电子发射断层扫描(PET)的最大标准摄取值(SUVmax)在诊断≥14.9(HR6.802;[1.233,37.519];P = 0.028)。结论起病时患者EBV-DNA阳性、低白蛋白血症和高SUVmax三者可预测成人HLH的早期死亡。如果出现这些高危因素,早期积极的干预可能使患者从中受益。第二部分自体造血干细胞移植在成人淋巴瘤相关的噬血细胞淋巴组织细胞增多症中的应用目的淋巴瘤相关的HLH(LAHS)特点是少见、异质性强以及死亡率高。目前尚无标准治疗方案可循。对于后续的移植,临床报道极少,大部分参照儿童HLH的治疗方案。对于大部分患者,临床上选择异基因造血干细胞移植来巩固、强化治疗,目标为治愈该病,但是移植相关死亡率高、供体难寻以及年龄因素等因素限制其广泛使用。自体造血干细胞移植(ASCT)在成人淋巴瘤相关的噬血细胞淋巴组织细胞增生症(HLH)中的作用一直不明确。本文的目的在于探讨ASCT治疗HLH中的疗效。方法2009年9月至2016年9月在我院血液科住院的LAHS经化疗联合ASCT的患者有8例。8例中男3例、女5例,中位年龄为52.5岁(范围:21～64岁),中位随访时间为10个月(18～59个月)。患者对初始化疗方案有效并取得缓解后,给予动员采集外周血造血干细胞进行ASCT。7例患者的预处理方案为BEAM方案,另外1例为CBV方案。回顾性分析8例淋巴瘤相关的HLH患者使用自体造血干细胞移植治疗的效果。结果患者起病的中位年龄为54.5岁(21～64岁);3例男性和5例女性。8例患者中,外周T细胞淋巴瘤为2例,5例为B细胞非霍奇金淋巴瘤(其中1例为弥漫大B细胞淋巴瘤),还有1例未明确细胞来源。在8例患者中,7例可见骨髓侵犯。所有患者的乳酸脱氢酶均升高。根据国际预后指数,所有患者均为高危患者(高-中危4例;高危4例)。2例患者的EBV-DNA为阳性。7例患者接受剂量调整的EPOCH方案诱导化疗,另1例为CHOP方案。如系B细胞淋巴瘤,则联合利妥昔单抗治疗。移植前患者经过化疗,6例患者取得了完全缓解(CR),2例取得部分缓解;移植后,8例患者均为完全缓解。没有移植相关死亡发生。中位随访54.5个月(范围:18～59月),所有患者均存活且处于CR中。结论一线选择EPOCH方案后续以BEAM方案预处理行ASCT可能是一种有效的治疗选择,从而改善淋巴瘤相关HLH患者的预后。第三部分103例成人噬血细胞淋巴组织细胞增多症的靶向基因测序研究目的噬血细胞淋巴组织细胞增多症(HLH)分为原发性HLH与继发性HLH两种类型。原发性HLH通常好发于儿童,并可能具有杀伤细胞功能相关的基因突变。迄今为止,成人HLH是否具有原发性HLH相关性遗传学异常尚不清楚。方法利用Illumina Miseq或Nextseq在103例成人HLH的进行了原发HLH相关基因测序。测序的基因包括PRF1、UNC13D、STXBP2、STX11、RAB27、LYST和AP3B1等18个基因,测序深度为1000×。在正常东亚人群中出现频率低于1%的突变或变异位点纳入进一步研究。结果入选的103例患者中,男63例,占61.2%;女40例,占38.8%,男、女比例为1.5:1。中位发病年龄为48岁,年龄范围18～85岁之间。103例患者中,22例为感染相关HLH,61例为肿瘤相关(59例为淋巴瘤)HLH,3例为自身免疫性疾病相关HLH,17例患者为原因不明的成人HLH。共在43例患者中检测到噬血相关基因的突变位点,其中1例患者具有纯合突变位点(UNC1c.G2588A[P.G863D]),2例患者具有复合杂合突变,3例患者具有双杂合位点突变。在检测到的变异位点中,共有检测到7个重现性变异位点,分别为UNC13D P.G863D、ITK p.R581 W、AP3B1p.T310A、STXBP2 p.T163M、UNC13D p.R411Q、LYST p.H123R及STX11 p.F281C突变。在这些位点中,其中UNC13D p.G863D在103例HLH的出现的频率高于正常东亚人群(3/206[1.5%]对37/8638[0.4%],比值比[OR]4.514,95%可信区间[CI]1.054-11.28;p=0.0651),尽管该结果尚不具有统计学意义,AP3B1 p.T310A出现的频率也显著高于正常东亚人群(2/206 对 2/8648,OR 42.98,95%CI 5.938-302.5,p0.0001),ITKp.R581W的突变频率在本组患者中的频率也要高于正常东亚人群(4/206[2.0%]对70/8652[0.8%],OR 2.428,95%CI 0.878-6.715,p=0.093),此外 STX11 P.F281C的频率在本组患者中出现的频率也显著高于东亚人群(2/206[0.97%]对1/8382[0.01%],OR160.0,p=0.0005),提示这些位点与HLH的发生相关。而对于STXBP2 p.T163M、UNC13D p.R411Q及LYSTp.H123R则没有发现其分布频率上在本组患者和东亚人群之间有显著差异。结论成人HLH亦具有原发性HLH相关的遗传学异常,利用靶向测序进行HLH相关基因筛查可以用于成人HLH的辅助诊断。
[Abstract]:The first part of adult hemophagocytic lymphoid cell lymphohistiocytosis, most of the adult hemophagocytic lymphohistiocytosis (AHLH) is secondary, and the clinical symptoms of a small part of the delayed type FHLH.AHLH are varied, but there is no specificity. The general manifestations are hyperthermia, liver and spleen enlargement, hemocytosis, abnormal coagulation function, and high glycerin oil three. Hyperglycemia, hyperferremia, Hyperferritinemia, hyperlactate dehydrogenase, and multiple organ failure have not been found so far. The clinical data of 327 adult HLH patients in our hospital were collected and analyzed to explore the clinical features, treatment and identification with early death. The risk factors of HLH were strengthened by clinicians. Methods the detailed clinical data of the patients were collected, the results of the laboratory examination were collected, and the patients were followed up with the telephone form. The follow-up deadline was 2016-03-31.327 patients, 8 cases were lost and the follow-up rate was 97.6%. The date of death was the deadline of study, the loss of visits or cut-off follow. The patients were still classified as Censorship (also called truncation or final examination). The retrospective analysis method was used, the count data were expressed in proportion or percentage, and the Cox regression model was used to analyze the related factors by single factor analysis. The factors of statistical significance were screened by multi factor analysis. The survival curve was drawn by Kaplan-Meier method and the median survival time was estimated. Between groups, the survival rate was compared with Log-Rank test, and P0.05 was considered to be statistically significant. Results the median age of 327 patients in the group was 53 years (18~93 years old), of which 181 were male and 146 female. Most of the patients showed fever, liver, spleen and lymph nodes were enlarged and the blood cell phagocytosis of.133 (42%) in the bone marrow specimens (42%) was 8 after diagnosis. The secondary factors included infection (n= 129; 39%), blood system tumor (n=107; 33%), unexplained cause (n = 68; 21%) and autoimmune diseases (n = 21; 7%). This study was followed up with (1) EBV-DNA positive (HR3.594,95%CI; [1.443,8.952]; P=0.001), and (2) low proteinemia (HR 1.10[1.01,1.20]; P = 0.046). And (3) the maximum standard uptake value (SUVmax) of positron emission tomography (PET) is more than 14.9 (HR6.802; [1.233,37.519]; P = 0.028). Conclusion patients with EBV-DNA positive, hypoalbuminemia, and high SUVmax three can predict early death of adult HLH. If these high-risk factors occur, early active intervention may lead to patients. Benefit. Second parts of autologous hematopoietic stem cell transplantation in adult lymphoma related hemophagocytic lymphohistiocytosis. Objective lymphoma related HLH (LAHS) characteristics are rare, heterogeneity and high mortality. There is no standard treatment yet to follow. Few clinical reports for subsequent transplantation, most of the references HLH treatment for children. For most patients, allogeneic hematopoietic stem cell transplantation is selected to consolidate and strengthen the treatment. The goal is to cure the disease, but the high mortality rate, difficult donor search, and age factors are widely used. Autologous hematopoietic stem cell transplantation (ASCT) is used in adult lymphoma related hemophagy. The role of cytosycyhistiocytic cell proliferation (HLH) is not clear. The purpose of this article is to explore the effect of ASCT in the treatment of HLH. Methods from September 2009 to September 2016, there were 8 cases of.8 cases in the Department of Hematology of our hospital in the Department of Hematology with ASCT, male 3, female 5, the median age of 52.5 years (range: 21~64 years), and the median follow-up time For 10 months (18~59 months). After the patients were effective and remission of the initial chemotherapy regimen, the preconditioning regimen of mobilizing and collecting peripheral blood hematopoietic stem cells for ASCT.7 patients was BEAM scheme and 1 cases were CBV. The results of 8 cases of lymphoma related HLH patients treated with autologous hematopoietic stem cell transplantation were retrospectively analyzed. The median age of the patient was 54.5 years (21~64 years); of 3 men and 5 women with.8, peripheral T cell lymphoma was 2, 5 cases were B cell non Hodgkin's lymphoma (1 of the diffuse large B cell lymphoma), and 1 undefined cell sources. In 8 patients, bone marrow invasion was seen. All patients with lactate dehydrogenase were all According to the international prognostic index, all patients were high risk patients (high risk 4 cases, high risk 4; high risk 4 cases), EBV-DNA was positive.7 patients received dose adjusted EPOCH regimen chemotherapy, the other 1 were CHOP scheme, such as B cell lymphoma, combined with rituximab. The pre transplant patients were treated with chemotherapy and 6 patients obtained Complete remission (CR), 2 cases had partial remission; after transplantation, 8 patients were completely remitted. No transplant related death occurred. The median follow-up was 54.5 months (range: 18~59 months), all patients survived and were in CR. Conclusion a first-line selection of EPOCH regimens followed by BEAM regimen preconditioning may be an effective treatment option, thereby modifying the treatment. The prognosis of HLH patients associated with good lymphoma. Third part 103 cases of target gene sequencing of hemophagocytic lymphohistiocytosis in adult patients. Target hemophagocytic lymphohistiocytosis (HLH) is divided into two types of primary HLH and secondary HLH. Primary HLH usually occurs in children, and may be associated with cytotoxic function. Gene mutation. To date, it is not clear whether adult HLH has primary HLH related genetic abnormalities. Methods the original HLH related genes were sequenced using Illumina Miseq or Nextseq in 103 adult HLH. The sequencing genes included PRF1, UNC13D, STXBP2, STX11, RAB27, and Miseq. The sequence was 1000 *. Among the 103 cases of common East Asia, there were more than 1% mutation or mutation sites in further study. Among the 103 patients enrolled, 63 were male, 61.2%, 40 women, 38.8%, male and female with 1.5:1. median age 48, and 18~85 years old among the patients, 22 were infection related HLH, 61 cases were tumor related (59 cases) Lymphoma) HLH, 3 cases of autoimmune disease related HLH, 17 cases of unexplained adult HLH. in 43 patients with the detection of mutation site of the blood related genes, of which 1 cases have homozygous mutation site (UNC1c.G2588A[P.G863D]), 2 cases with complex heterozygous mutation, 3 cases with double heterozygous site mutation. In the locus of variation, 7 reproducible loci were detected, such as UNC13D P.G863D, ITK p.R581 W, AP3B1p.T310A, STXBP2 p.T163M, UNC13D p.R411Q, LYST p.H123R and mutation. 4%], the ratio Ratio [OR]4.514,95% confidence interval [CI]1.054-11.28; p=0.0651), although the results are not statistically significant, the frequency of AP3B1 p.T310A appears significantly higher than the normal East Asian population (2/206 versus 2/8648, OR 42.98,95%CI 5.938-302.5, P0.0001), and the frequency of mutation is higher in this group than in the normal East Asia. The frequencies of the group (4/206[2.0%] to 70/8652[0.8%], OR 2.428,95%CI 0.878-6.715, p=0.093), and the frequency of STX11 P.F281C in this group were also significantly higher than those in the East Asian population (2/206[0.97%] for 1/8382[0.01%], OR160.0, p=0.0005). R did not find a significant difference in the frequency of distribution between the patients in this group and the East Asian population. Conclusion the adult HLH also has the genetic abnormalities associated with primary HLH, and the targeted sequencing of HLH related genes can be used for the adjuvant diagnosis of adult HLH.

【学位授予单位】：南京医科大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R733.1;R55

【参考文献】