老年套细胞淋巴瘤患者的治疗进展

套细胞淋巴瘤（MCL）是一种小B细胞非霍奇金淋巴瘤,好发于中老年人群。对于老年患者,利妥昔单抗+环磷酰胺+多柔比星+长春新碱+泼尼松（R-CHOP）方案、苯达莫司汀+利妥昔单抗（BR）方案、伊布替尼+利妥昔单抗（IR）方案及包含减量阿糖胞苷的方案都有较好的疗效和安全性。近年来,蛋白酶体抑制剂、Bruton酪氨酸激酶（BTK）抑制剂、B细胞淋巴瘤/白血病-2(Bcl-2)抑制剂和免疫调节剂纳入到老年MCL患者的治疗方案中,磷脂酰肌醇-3-激酶（PI3K）抑制剂、嵌合抗原受体T细胞疗法（CAR-T）的应用为复发难治性MCL患者提供了新的治疗选择。本文对老年MCL患者的治疗进展进行综述。     

套细胞淋巴瘤诊疗进展

套细胞淋巴瘤（mant lecell lymphoma ,MCL ）是一种少见的B 细胞非霍奇金淋巴瘤（non-Hodgkin's lymphoma,NHL ）类型,兼具有惰性淋巴瘤和侵袭性淋巴瘤的临床病理特点。目前MCL 的临床治疗仍然是以全身化疗为主,含有阿糖胞苷的强诱导化疗,随后行自体造血干细胞移植（autologous stem cell transplantation,Auto-HSCT ）巩固,可以显著延长生存期,但MCL 仍然属于不可治愈的淋巴瘤类型。近年来,随着对MCL 发病机制的深入研究,更多的新药如Btk抑制剂、PI 3K 抑制剂、免疫调节剂等在MCL 中得到应用。初治、复发难治MCL 都具有更多的治疗选择,如何将新药和现有的化疗更为有机的结合,更好的改善MCL 患者的生存期是未来研究的重点。     

套细胞淋巴瘤的诊治进展

套细胞淋巴瘤(MCL)是一组以t(11;14)和细胞周期蛋白D1阳性(cyclinD1 )过度表达为特征的侵袭性非霍奇金淋巴瘤(NHL),约占NHL发病的5%~8%,预后差,近期通过比较基因组杂交(CGH),基因芯片和蛋白质组分析等研究MCL取得令人关注的进展。化疗 利妥昔治疗使治疗有效率较前明显提高,异体或自体干细胞移植亦使MCL的预后大为改善,新的治疗方案如蛋白酶体抑制剂硼替佐米(borte-zomib),反应停 利妥昔,细胞周期依赖激酶抑制剂(flavopridol)及哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂CCI-779等的疗效令人鼓舞。     

套细胞淋巴瘤的靶向治疗

 套细胞淋巴瘤（MCL）是最令人失望的疾病之一，因其具有侵袭性非霍奇金淋巴瘤（NHL）及惰性NHL的不良特征，前者进展迅速，后者难以治愈，且缺乏最佳治疗选择。临床研究证实利妥昔单抗单用或与化疗联合方案治疗MCL有效。波替单抗治疗MCL也有效，在联合方案中尚需进一步研究。哺乳动物雷帕霉素抑制剂与放射免疫治疗MCL代表一种新的治疗方法，值得进一步研究。     

硼替佐米联合氟达拉滨及环磷酰胺治疗复发难治性套细胞淋巴瘤完全缓解2例并文献复习

套细胞淋巴瘤(mantle cell lymphoma,MCL)是一种具有高度侵袭性的起源于淋巴结滤泡套区的B细胞非霍奇金淋巴瘤(non-Hodgkin's lymphoma, NHL),占NHL的3％～10％,高发于老年人群,中位发病年龄为60～65岁,男女比例为3:1[1].MCL具有特征性的遗传学易位特点t(11;14)(q13;q32),细胞周期蛋白D1(CyclinD1)过表达,恶性程度高,中位生存时间为3～5年[2].目前尚无标准的治疗方案,常以环磷酰胺+多柔比星+长春新碱+强的松(CHOP)方案为主,可获得较高的缓解率,但复发率高.硼替佐米是一种新型的蛋白酶体抑制剂,以硼替佐米为主的联合化疗目前成为MCL治疗领域研究的热点.天津市人民医院肿瘤诊治中心天津市中西医结合肿瘤研究所使用硼替佐米联合氟达拉滨及环磷酰胺治疗2例复发难治MCL患者并获得了完全缓解,现报道如下.     

套细胞淋巴瘤诊治新进展

套细胞淋巴瘤(mantle cell lymphoma,MCL)是一种特殊的淋巴瘤亚型,兼具惰性淋巴瘤的难治愈性以及侵袭性特征.多见于老年,中位发病年龄58岁,男女比例约为2:1.中国抗癌协会淋巴瘤病理专家组统计了21 127例淋巴瘤患者资料,MCL占非霍奇金淋巴瘤(Non-Hodgkin's Lymphoma,NHL)的5%.虽然已经有较多新药用于MCL的治疗,但总生存期(overall survival,OS)并没有明显延长[1],中位生存期为4～6年.     

老年套细胞淋巴瘤研究进展

套细胞淋巴瘤(mantle cell lymphoma,MCL)是一种独特的B细胞淋巴瘤,占非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL)的3％～10％,除自体干细胞移植(ASCT)外,MCL无其它可治愈的手段.MCL多见于老年男性,多数老年患者常合并基础疾病而不能耐受大剂量化疗和ASCT.全文主要分析MCL的病理生理、治疗、风险分层、预后以及老年患者的治疗选择.     

硼替佐米治疗套细胞淋巴瘤的分子学机制

 套细胞淋巴瘤（MCL）是生存期最短的非霍奇金淋巴瘤（NHL）,目前尚不能根治。硼替佐米是第一个用于治疗血液系统恶性肿瘤的蛋白酶体抑制剂,主要用于多发性骨髓瘤（MM）及复发难治性MCL的治疗。探讨硼替佐米治疗MCL的相关机制,其中包括调节细胞周期、影响细胞凋亡、干扰MCL的微环境以及与其他抗肿瘤药物的协同作用等,有助于未来合理应用硼替佐米治疗MCL。     

替西罗莫司治疗套细胞淋巴瘤的研究进展

套细胞淋巴瘤（MCL）是一种少见、独特的B细胞非霍奇金淋巴瘤（NHL）亚型.现有不少治疗MCL的药物和方案,均有一定疗效,但疗效维持时间短,不够理想.目前认为MCL是难以治愈的,预后不良.文章着重介绍了一种治疗MCL的新药替西罗莫司.该药是雷帕霉素的衍生物,它通过下调淋巴瘤的Cyclin D1和Ki-67,阻断细胞周期,诱导肿瘤缩小,抑制肿瘤生长.研究显示替西罗莫司能诱导MCL患者缓解和延长生存,特别对复发性或难治性MCL患者有一定疗效.另外,替西罗莫司与利妥昔单抗,或与其他化疗药物联合应用,能获得比单用替西罗莫司更好的效果.     

滤泡淋巴瘤治疗进展:第56届美国血液学会年会报道

滤泡淋巴瘤(FL)是一种起源于滤泡生发中心的惰性非霍奇金淋巴瘤(NHL).在2014年12月召开的第56届美国血液学会年会上,多篇研究报道了FL治疗的最新进展.放疗在早期FL的疗效依旧被肯定,GA101联合化疗治疗中晚期FL的临床试验结果亦鼓舞人心;利妥昔单抗年代造血干细胞移植仍给复发难治的FL患者带来更优的缓解,BTK、PI3K抑制剂等新药随着相应临床试验的进展也树立了治疗复发难治FL的新路标.     

Proteasome inhibition with bortezomib: a new therapeutic strategy for non-Hodgkin's lymphoma

The incidence of non-Hodgkin's lymphoma (NHL) has markedly increased in the US and other westernized countries in recent years and presents a considerable clinical challenge. NHL is divided into subtypes that follow an aggressive or indolent course. Follicular lymphoma (FL), the most common indolent subtype, and mantle cell lymphoma (MCL), an aggressive subtype that accounts for approximately 5% of cases, are generally incurable. MCL has a relatively poor prognosis, with a median survival of 3-4 years. Despite improving response rates with new agents and regimens, the lack of demonstrated improvement in overall survival in many subtypes supports the development of novel approaches, such as proteasome inhibition. Bortezomib is the first proteasome inhibitor to be evaluated in human studies. It has already been approved as second-line treatment in multiple myeloma and is now under active investigation in NHL. The US FDA has granted bortezomib fast-track designation for relapsed and refractory MCL. In vitro and in vivo studies have demonstrated single-agent activity against various lymphoid tumors, and additive or synergistic effects in combination with other agents, including standard chemotherapy drugs employed in NHL. Phase 2 clinical trials indicate that bortezomib is well tolerated and active in several NHL subtypes, with response rates of 18-60% in FL and 39-56% in MCL. A number of combination trials are currently underway with a range of standard agents. Bortezomib has the potential to play a significant role throughout the NHL treatment algorithm in the future.     

The microenvironment in mantle cell lymphoma: cellular and molecular pathways and emerging targeted therapies

There is growing evidence suggesting that cross talk between mantle cell lymphoma (MCL) cells and stromal cells in tissue microenvironments, such as the bone marrow and secondary lymphoid organs, causes disease progression by promoting lymphoma cell survival, growth, and drug resistance. Conceivably, while conventional treatment eliminates the bulk of MCL cells, residual lymphoma cells may lurk in protective tissue niches, where they receive signals from accessory cells that promote survival and drug-resistance, thereby paving the way for residual disease and relapses. Based on this concept, the lymphoma microenvironment has become a growing area of current research, and initial clinical trials targeting cross talk between MCL cells and their microenvironment are showing promising early results. In this review, we summarize key cellular and molecular interactions between MCL cells and their microenvironment, and update new clinical developments in this area.     

Evaluation and management of the “New” lymphoma entities: Mantle cell lymphoma, lymphoma of mucosa-associated lymphoid tissue, anaplastic large-cell lymphoma, and primary mediastinal B-cell lymphoma

Non-Hodgkin's lymphomas (NHL) represent a major health problem worldwide, and incidence has been on the rise continuously for the last few decades. It is estimated that approximately 55,000 new cases of NHL will be diagnosed in the United States in 1998 and that slightly fewer than 25,000 patients will die of treatment failure or recurrent disease. The rising incidence of NHL is related not only to the acquired immunodeficiency syndrome epidemic but to also a steady increase in the number of cases diagnosed in older patients without immunosuppression. The new pathologic classification of NHL (revised European-American lymphoma classification, REAL) developed by the International Lymphoma Study Group (ILSG) is already resulting in more accurate disease-specific epidemiologic and clinical investigations. These studies have brought a new awareness of the existence and the relative prevalence of discrete NHL subtypes that appear to predominate among patients in different populations according to age, sex, geographic distribution, and predisposing conditions. This developing database has also the potential to result in the discovery of specific environmental causes, predisposing genetic factors, and therapeutic approaches. Some of the entities defined in the REAL classification, such as follicular lymphomas, diffuse B large-cell lymphomas, and T-cell lymphoblastic lymphomas, were already well described in the older classification systems (Kiel and Working Formulation). Others, such as mantle cell lymphoma, (MCL) anaplastic large-cell lymphoma (ALCL), lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), and primary mediastinal B-cell lymphoma (PMBCL) are relatively new members of the family, and accurate data on their clinicopathologic features and natural histories have only recently begun to emerge.This review presents in detail the most recent data on the clinical presentation of, diagnostic evaluation of, and treatment options for the most common of the new NHL entities: MCL, MALT lymphoma, CD30⁺ (Ki-1⁺) ALCL, and PMBCL. These four entities combined represent approximately 20% of all cases of NHL and exemplify well the broad clinicopathologic spectrum of NHL and the diagnostic and therapeutic challenges facing those who care for patients affected by these conditions.     

Altered apoptosis pathways in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive subentity of non-Hodgkin lymphoma (NHL), responds poorly to therapy, is resistant to current therapeutic strategies and has the shortest survival of all lymphoma entities. The blastoid variant of mantle cell lymphoma (MCL-BV) has an even worse clinical outcome. The mechanisms of neoplastic transformation from normal mantle cells and the relationship to the rare blastoid variant are poorly understood. BCL2 is overexpressed in indolent B-cell NHL including MCL. In addition, other proteins of the BCL-family are overexpressed in MCL like BCLX, whereas the expression of BAX and BAK was not elevated in MCL. BCL2 independent apoptotic pathways are altered in MCL. CD40, which can mediate B-cell survival, is overexpressed in MCL. Furthermore, the expression of FAS which is known to be pro-apoptotic is markedly decreased favoring the CD40 mediated cell survival pathway in these cells. Besides overexpression of cyclin D1, the cyclin dependent kinases (CDK2 and CDK4) are highly expressed in MCL resulting in the phosphorylation of RB1, E2F release, and the cell cycle progression. The new technique of gene expression analysis by microarrays promotes more insight into the pathogenesis of MCL and discovery of altered cell signaling pathways, and the ability to predict subgroups of patients with different risk and probability of response to treatment.     

Marked clinical activity of the proteasome inhibitor bortezomib in patients with follicular and mantle-cell lymphoma

Recent advanced developments in our understanding of cancer cell biology have begun to generate a host of new targets that are proving to be valuable substrates for new drug development. One example includes our ever-increasing understanding of the complex biology surrounding the ubiquitin-proteasome pathway. For years there have been a variety of compounds used in the laboratory that have been shown to inhibit the proteasome, though many of these compounds have proven to be relative non-specific inhibitors of intracellular and proteasome proteases. The recent synthesis of 1 novel inhibitor, bortezomib (formerly known as PS341), has proven to be an effective reversible inhibitor of the chymotryptic protease in the 26S proteasome. Proteasome inhibition represents a new approach for the treatment of many forms of cancer, especially select hematologic malignancies. Bortezomib has been approved by the United States Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. In addition to myeloma, bortezomib has also shown promising activity in the treatment of select types of non-Hodgkin's lymphomas (NHLs). Several single-agent phase II clinical trials in patients with a host of different NHL histologies have demonstrated that bortezomib has reproducible activity in mantle-cell lymphoma (MCL) and follicular lymphoma (FL), with some suggestion of activity in marginal zone lymphoma. The promising activity in these smaller studies has led to a number of larger multicenter studies with bortezomib in combination with rituximab in MCL, FL, and marginal zone lymphoma. The collective early experience from these studies continues to support the activity of bortezomib in these histologies of NHL. Herein, some of the biologic rationale for using proteasome inhibitors in lymphoma as well as some of the clinical data from these promising studies are discussed.     

高度侵袭性非霍奇金淋巴瘤的规范化治疗

 经典CHOP方案不是所有非霍奇金淋巴瘤（NHL）的最佳治疗方案,特别是对于高度侵袭性NHL。Burkitt淋巴瘤的标准治疗为高剂量、短疗程的多药联合化疗（如CODOX-M／IVAC±R、R-HyperCVAD／MA）及中枢神经系统白血病（CNSL）的预防。淋巴母细胞淋巴瘤应采取同急性淋巴细胞白血病（ALL）的治疗策略。而对于套细胞淋巴瘤（MCL）,利妥昔单抗联合含大剂量阿糖胞苷方案化疗缓解后,巩固以自体细胞移植（ASCT）是目前对能耐受患者的一线治疗共识。     

套细胞淋巴瘤诊治进展

套细胞淋巴瘤（MCL）是小 B 细胞淋巴瘤中一组高侵袭性的非霍奇金淋巴瘤（NHL）,约占NHL 的6%。MCL 起病隐匿、侵袭性强、恶性程度高、预后差,因此,MCL 的诊断及鉴别诊断至关重要。另外,MCL 分子病理模型、细胞周期蛋白 D1阴性 MCL、MCL 分期预后及分层治疗选择均值得关注。     

Bortezomib: clinical profile in lymphoproliferative malignancies

In addition to its efficacy in the treatment of multiple myeloma, the proteasome inhibitor bortezomib appears to be active against a variety of other haematological malignancies. In a phase II trial, bortezomib, given twice weekly for 2 weeks of a 3 week cycle to patients with relapsed, refractory or untreated indolent non-Hodgkin's lymphoma (NHL) or mantle cell lymphoma (MCL), produced durable responses in 2/7 MCL patients and stable disease in five. Six of eight patients with follicular NHL achieved a durable response (1 CR, 5 PR). In another study, bortezomib was administered to patients with relapsed or refractory indolent or aggressive B-cell lymphoma. Durable responses were seen in 7/12 MCL patients, including three CR. This apparent activity in MCL is particularly encouraging, given its poor prognosis. These early trial results demonstrate that further clinical testing of bortezomib and additional exploration of the multiple biologic effects of proteasome inhibition are warranted in lymphoproliferative malignancies.     

Pathologic Diagnosis of Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a clinicopathologic entity with distinctive morphologic and immunophenotypic features and a characteristic cytogenetic abnormality, the t(11;14)(q13;q32). Although MCL was recognized over 30 years ago, a lack of consensus regarding its morphologic features precluded its inclusion into non-Hodgkin's lymphoma (NHL) classification schemes until relatively recently. An accurate diagnosis of MCL is of great importance, since this tumor generally carries a poor prognosis and requires more aggressive and novel treatment regimens. In this article, we briefly overview the clinical features of MCL and then focus on the pathologic diagnosis of MCL, emphasizing morphologic findings and various ancillary techniques useful in the diagnostic workup. Involvement of lymph nodes and other sites, such as the spleen, liver, gastrointestinal tract, Waldeyer's ring, bone marrow, peripheral blood, and cerebrospinal fluid are reviewed. The diagnosis of high-grade variants of MCL is a particular challenge, as these tumors exhibit a broad spectrum of morphologic findings that can be misinterpreted as other types of NHL. The molecular basis of MCL is also briefly reviewed to highlight the biologic role of the t(11;14) and cyclin D1 overexpression in this tumor and the value of immunophenotypic and molecular methods for their detection as diagnostic aids.