弥漫性大B细胞淋巴瘤的治疗选择

弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphpma，DLBCL）是非霍奇金淋巴瘤中最常见的类型，在分子遗传学、免疫表型等方面具有高度异质性，患者临床预后也截然不同。R-CHOP方案为DLBCL标准治疗方案，如何进一步提高DLBCL疗效是近年来的研究热点。2015年美国临床肿瘤学会（ASCO）提出基于细胞起源分型进行R-CHOP+X方案治疗的策略，但这些方案相继失败。基于更加精准的分层方法，筛选出不同DLBCL亚组并进行针对性治疗，是未来DLBCL治疗的方向。此外，抗体-药物偶联物、双特异性抗体和嵌合抗原受体T细胞（chimeric antigen receptor T-cell，CAR-T）等免疫治疗近年来取得突破性进展，为DLBCL患者带来新的希望。本文针对基于精准分层的DLBCL靶向治疗、免疫治疗的最新进展及遗传学检测方法予以综述。      

双重打击弥漫性大B 细胞淋巴瘤的临床病理研究进展

弥漫性大B 细胞淋巴瘤（diffuse large B-cell lymphoma,DLBCL ）是一种具有高度异质性的淋巴造血系统恶性肿瘤,目前用标准化疗方案治疗的多数DLBCL 患者可以被治愈,但仍有30% ～40% 的DLBCL 患者治疗后复发或难以治愈而死亡。双重打击淋巴瘤（double-hit lymphoma ,DHL ）主要发生于DLBCL 及介于DLBCL 和伯基特淋巴瘤（Burkitt's lymphoma ,BL）之间无法分类的B 细胞淋巴瘤（B-cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt's lymphoma ,BCLU）为生存期短、预后差、易复发的一种独特类型,是近年来的研究热点。虽然BCLU更容易发生DHL ,但DLBCL 是DHL 最常见的淋巴瘤,因此本文旨在对双重打击弥漫性大B 细胞淋巴瘤（double hit-DLBCL ,DH-DLBCL ）的流行病学和临床特征、诊断、分子遗传学及其治疗和预后特点等方面进行综述。      

复发难治性弥漫大B细胞淋巴瘤靶向药物治疗进展

淋巴瘤为一组起源于淋巴结或其他淋巴组织的异质性血液系统恶性肿瘤，包括霍奇金淋巴瘤（Hodgkin's lymphoma，HL）和非霍奇金淋巴瘤（non-Hodgkin's lymphoma，NHL），其中弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphoma，DLBCL）为一类异质性明显的淋巴系统恶性肿瘤，也是最常见的NHL亚型。标准R-CHOP方案（利妥昔单抗联合环磷酰胺、阿霉素、长春新碱和泼尼松）治疗可显著提高60%以上患者的生存期，然而仍有约30%~40%患者出现疾病复发或难治，预后较差，如何延长复发难治性DLBCL患者的生存期并改善其预后已成为目前国内外研究的热点。随着疾病基因表达谱、耐药分子机制等的不断深入研究，化疗新方案及新药不断探索，为个体化精准治疗复发难治性DLBCL带来新希望。本文拟对新近的靶向药物在复发难治性DLBCL中的治疗进展进行综述。      

美罗华联合化疗治疗弥漫性大B细胞淋巴瘤七例报告

美罗华（Rituximab）于1990年被研制成功，可特异性地与B淋巴细胞表面CD20抗原结合，是人鼠嵌合型单克隆抗体。主要用于治疗复发的低度恶性或滤泡型非霍奇金淋巴瘤（diffuse large-B-cell lymphoma，DLBCL）。对B细胞淋巴瘤具有良好的疗效，有效率为40％～50％，美罗华和化疗合用有效率达90％以上。我们近3年使用美罗华共治疗7例弥漫性大B细胞DLBCL患者，结果报道如下。     

复发难治性弥漫大B细胞淋巴瘤研究进展

近年来非霍奇金淋巴瘤(NHL)的发病率呈上升趋势,弥漫大B细胞淋巴瘤(DLBCL)是其中的主要类型.利妥昔单抗联合化疗虽获得了明显疗效,但目前仅有10%复发难治性DLBCL患者有治愈机会,且治疗方法有限.文章从复发难治性DLBCL的发病与耐药机制、二线治疗中的个体化选择、新药及新药联合的疗效、针对不同亚型与耐药机制的靶向药物、免疫检查点抑制剂及嵌合抗原受体T细胞免疫疗法的应用及复发难治性DLBCL复发监测等方面作一综述.     

靶向药物治疗弥漫大B细胞淋巴瘤研究进展

弥漫大B细胞淋巴瘤(DLBCL)是侵袭性淋巴瘤中最常见的亚型, 复发难治DLBCL患者预后较差, 临床尚缺少有效的标准治疗方案。如何对复发难治DLBCL患者进行有效治疗一直是研究的热点, 目前的新药/技术研究包括双特异性抗体治疗、嵌合抗原受体T细胞(CAR-T)疗法、抗体偶联药物(ADC)治疗等。文章就第64届美国血液学会(ASH)年会关于DLBCL的靶向药物/细胞治疗进展进行综述。     

ALK+弥漫大B 细胞淋巴瘤患者临床决策探讨*

ALK+弥漫大B 细胞淋巴瘤（anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma ,ALK+DLBCL ）是淋巴瘤中一种罕见的和具有明显差异性的病理类型,2008年WHO将其归类为DLBCL 一个独特的亚型,该病侵袭性高,容易复发,目前尚无规范有效的治疗方案。采取多学科协作体系（multidisciplinary treatment ,MDT ）有利于制定规范化、个体化的治疗方案,探索针对ALK+DLBCL 患者更有效的治疗方法,从而让更多的患者获益。本研究分享1 例2012年1 月天津医科大学肿瘤医院收治的ALK+DLBCL 高剂量化疗联合自体造血干细胞移植（autologous hematopoietic stem cell transplantation ,AHSCT）后复发,采用ALK 激酶抑制剂克唑替尼（Crizotinib ）治疗成功的案例。      

复发弥漫性大B细胞淋巴瘤血清血管内皮细胞生长因子的表达及其临床意义

目的探讨复发弥漫性大B细胞淋巴瘤（DLBCL）血清中血管内皮生长因子（VEGF）的表达及其临床意义。方法采用酶联免疫吸附法（ELISA）对23例复发DLBCL患者及23例正常体检者（对照组）进行血清VEGF测定。结果复发的DLBCL患者VEGF水平高于对照组（P〈0.01）;Ⅲ、Ⅳ期患者高于Ⅰ、Ⅱ期患者（P〈0.01）;GCB组VEGF水平高于N-GCB组（P〈0.01）。ESHAP＋利妥昔单抗＋自体干细胞移植（ASCT）组经治疗后患者血清VEGF水平下降至正常或接近正常,与治疗前比较,差异有统计学意义（P〈0.01）。结论血清VEGF可作为复发DLBCL的一种监测指标,反映复发DLBCL的疾病状态,对判断病情、预测复发、指导治疗具有一定临床意义。     

儿童散发性伯基特淋巴瘤的研究进展

 【摘要】　儿童散发性伯基特淋巴瘤（BL）属于高度侵袭性淋巴瘤,在形态学、免疫表型和分子遗传学等方面与弥漫性大B细胞淋巴瘤（DLBCL）及介于DLBCL和BL之间的未分类B细胞淋巴瘤（DLBCL／BL）有部分重叠,但亦有其独特的表征。通过对BL病理、发病机制及预后的了解,增强对该病的认识,并在诊断时与DLBCL、DLBCL／BL进行鉴别,有利于临床正确的治疗及预后判断。     

弥漫性大B细胞淋巴瘤血清生物标志物的研究进展

弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphoma，DLBCL）作为最常见的侵袭性非霍奇金淋巴瘤具有较大的异质性。治疗前期及治疗过程中对患者进行有效的预后评估尤为重要。随着分子基因学及免疫治疗的迅速发展，传统的预后评估手段受到了极大的挑战，综合多种方法对患者进行精准的预后评估至关重要。近年来，多种血清生物标志物在DLBCL的预后评估中受到关注。血清生物标志物以无创、便捷和灵敏度高等优点更易于被患者接受，其在DLBCL预后综合评估中的作用不可忽视。本文就血清生物标志物在DLBCL中的研究进展进行综述。      

Rituximab therapy in malignant lymphoma

Rituximab is the first monoclonal antibody to have been registered for the treatment of B-cell lymphomas. Randomized studies have demonstrated its activity in follicular lymphoma (FL), mantle cell lymphoma and diffuse large B-cell lymphoma (DLBCL) in untreated or relapsing patients. Non-comparative studies have shown an activity in all other lymphomas. Because of its high activity and low toxicity ratio, rituximab has transformed the outcome of patients with B-cell lymphoma. A combination of rituximab plus chemotherapy, rituximab+cyclophosphamide+doxorubicin+vincristine+prednisolone (R-CHOP), has the highest efficacy ever described with any chemotherapy in DLBCL and FL. Some patients are refractory to rituximab but the precise mechanisms of this refractoriness are not understood.     

弥漫大B细胞淋巴瘤研究最新进展

弥漫大B细胞淋巴瘤(DLBCL)是成年人发生率最高的淋巴瘤亚型,是一组高度异质性的肿瘤,不同亚型有不同的生物学特征、临床表现及治疗反应,患者预后差别很大,尽管目前的标准治疗R-CHOP方案为基础的免疫化疗使DLBCL治愈率提高,但仍有约40％的患者治疗早期即出现耐药或达到缓解后复发,预后差.本文结合第59届美国血液学会(ASH)年会有关报道,对DLBCL的新分子分型、新靶点药物研发、复发难治患者治疗等的研究进展进行总结.     

复发难治性弥漫大B细胞淋巴瘤的生物靶向治疗

含有利妥昔单抗的化疗方案能改善弥漫大B细胞淋巴瘤(DLBCL)患者的预后,然而仍有部分患者在一线应用R-CHOP方案后转为复发难治性DLBCL(RR-DLBCL),且预后不良.对DLBCL及其相关肿瘤基因表达研究证实基因水平的生物靶向治疗能改善RR-DLBCL患者的预后.目前,一些新的靶向治疗成为研究热点.文章就RR-DLBCL的生物靶向治疗进展进行综述.     

Improving outcomes for patients with diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world. Until the mid 1990s the incidence of DLBCL increased in both sexes, across racial categories, and across all age groups except the very young, the etiology of most cases remains unknown. DLBCL is associated with an aggressive natural history, but it can be cured with combination chemotherapy regimens like cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), which has been the mainstay of therapy for several decades. Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy. Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses, and the addition of the monoclonal antibody, rituximab, to CHOP has markedly improved outcomes. Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease.     

弥漫大B细胞淋巴瘤预后研究进展

弥漫大B细胞淋巴瘤(DLBCL)是最常见的非霍奇金淋巴瘤,具有高度异质性,高危患者预后差.如何更好地对DLBCL患者进行危险分层并早期识别高危患者是第58届美国血液学会(ASH)年会的一大热点.国际预后指数(IPI)作为经典的预后评分系统,在利妥昔单抗时代,其地位不断受到挑战,有多种新的预后评分系统被提出.分子生物学标记、基因突变在DLBCL的发生、发展中起重要作用,其预后价值备受关注.一些特殊DLBCL,如原发乳腺DLBCL、血管内大B细胞淋巴瘤、滤泡转化DLBCL以及复发难治DLBCL的预后也在该届年会上受到关注.     

Hitting back at lymphoma: How do modern diagnostics identify high-risk diffuse large B-cell lymphoma subsets and alter treatment?

Diffuse large B-cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease. Diagnostic tools in the clinic can now identify distinct subsets characterized by unique molecular features, which are increasingly transforming how these patients are managed. Activated B–cell-like DLBCL is characterized by NF-κB activation and chronic B-cell receptor signaling and may be targeted with lenalidomide or ibrutinib in the relapsed setting. Germinal center-like DLBCL is enriched for activating EZH2 mutations, and encouraging activity has been observed for the EZH2 inhibitor tazemetostat, which now has a fast-track US Food and Drug Administration designation. Double-hit lymphoma is a high-grade B-cell lymphoma characterized by translocations of MYC and BCL2 and/or BCL6 and carries a poor prognosis. Intensive chemoimmunotherapy strategies appear to be superior to standard R-CHOP (rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone) as initial therapy, and anti-CD19 chimeric antigen receptor T cells are inducing remission in patients with relapsed/refractory disease who previously had few available options. Primary mediastinal (thymic) large B-cell lymphoma is a molecularly distinct large-cell lymphoma with clinical and molecular features that overlap with those of classical Hodgkin lymphoma. R-CHOP has been associated with an unacceptably high rate of primary treatment failure in this young population, whereas dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab) produces durable remissions without the need for radiotherapy in most patients. For relapsed/refractory disease, immune checkpoint inhibitors targeting PD-1 have shown promising activity in chemotherapy-refractory disease, as have anti-CD19 chimeric antigen receptor T cells. Additional therapeutic targets, including JAK2, continue to be evaluated. The identification of discrete biological subsets is steadily moving us away from a “one-size-fits-all” approach in DLBCL.     

CD30在EBV阳性弥漫性大B细胞淋巴瘤中的表达及其预后意义北大核心

目的:探讨CD30在EBV阳性弥漫性大B细胞淋巴瘤(EBV-positive diffuse large B-cell lymphoma,EBV+DLBCL)中的表达及预后意义。方法:回顾性分析322例DLBCL中EBV+DLBCL与EBV-DLBCL病例临床病理参数之间的关系,以及CD30在EBV+DLBCL中的表达及预后意义。结果:CD30在EBV+DLBCL病例中的表达多于EBV-DLBCL病例(P=0.002);EBV-DLBCL中双表达的病例多于EBV+DLBCL(P=0.044);在63例EBV+DLBCL中,CD30阳性表达多见于B症状患者(P=0.015);另外有2例EBV+DLBCL病例出现BCL6基因重排。随访139例患者中,共表达CD30和EBER的患者预后较差(P=0.002);在EBV+DLBCL中,CD30阳性提示预后更差(P=0.028)。结论:CD30在EBV+DLBCL病例中具有较高的表达率,且与患者不良预后相关,进一步为靶向药物的使用提供理论依据。     

Lenalidomide combined with R-GDP in a patient with refractory CD5-positive diffuse large B-cell lymphoma: A promising response and review

CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) is associated with poor survival compared with CD5-negative DLBCL. The clinical characteristics of CD5+ DLBCL are different from both CD5-negative DLBCL and other CD5+ B cell lymphomas. There is currently no promising chemotherapy for CD5+ DLBCL. Herein, we report a 49-year-old Asian male with refractory CD5+ DLBCL. He complained of aggravated abdominal pain and weight loss. Computed tomography scan revealed abdominal masses, widespread lymphadenopathy, splenomegaly, and intussusception of the ileocecal junction with bowel wall thickening. Core needle aspiration biopsy of an abdominal mass was performed and immunohistochemistry revealed DLBCL of nongerminal center type. In this report, the dose-intensified R-Hyper CVAD (A) regimen as salvage therapy was introduced but failed to result in substantial improvement over the initially standard R-CHOP regimen. Next, the R-GDP regimen was administered as second-line treatment, but only resulted in a partial response. However, the addition of lenalidomide to R-GDP (R2-GDP) resulted in complete remission. The clinical features, pathogenesis, and possible mechanism of action of lenalidomide in CD5+ DLBCL have been described in the literature. The results of the present case report and literature searches indicate that CD5+ DLBCL may share a common pathway with activated B-cell like (ABC) DLBCL as determined by gene expression profiling. Lenalidomide is expected to induce favorable responses in patients with CD5+ DLBCL.