Clinical management of mantle cell lymphoma in the elderly

ABSTRACT

Introduction: Mantle cell lymphoma (MCL) is a disease with an indolent histology, but mostly aggressive clinical course. While treatment can yield more promising results in younger patients, the disease is most diagnosed at a median age of approximately 70 years, and treatment in this group still presents a major challenge for oncohematologists. Unfortunately, due to comorbidities and poorer general status, the implementation of intensive treatment approaches with the cytarabine-based regimens and autologous stem cell transplantation is generally not possible, and the disease remains incurable, especially in elderly patients.

Areas covered: In this paper, the authors discuss the therapeutic options available for older patients with MCL in the first line and relapsed/refractory settings, indicating new therapeutic options, which may achieve longer remissions and overall survival.

Expert opinion: Although great progress has been made in the treatment of MCL in recent years, there remains a need for new treatment lines which can allow improved patient outcomes. Novel agents targeting altered the signal transduction pathways in MCL cells may offer more promise than traditional chemotherapy or immunochemotherapy and are currently being tested in clinical trials.     

The preclinical discovery and development of bortezomib for the treatment of mantle cell lymphoma

Introduction: Mantle cell lymphoma (MCL) is an incurable, often aggressive B-cell malignancy. Bortezomib (BTZ), the 20S proteasome inhibitor was originally developed and approved for treatment of relapsed refractory multiple myeloma, and subsequently approved for treatment of MCL. BTZ’s single-agent activity induces clinical responses in approximately one-third of relapsed MCL patients. BTZ-containing combination therapies have further improved the quality and duration of clinical responses compared to standard chemotherapies in previously untreated MCL patients.

Areas covered: This review summarizes the discovery, mechanisms of -action and resistance, preclinical- clinical-developments, and FDA approval of BTZ for treatments of MCL.

Expert opinion: Preclinical MCL models demonstrated the apoptotic effect of BTZ through multiple mechanisms, as well as synergistic anti-MCL activity between BTZ and other chemotherapeutics. Single-agent and combinational clinical trials have validated the therapeutic potential of targeting the ubiquitin proteasome system (UPS) in MCL. However, inherent and acquired drug resistance remains a significant clinical problem and multiple potential mechanisms have been identified. Next-generation proteasome inhibitors with different pharmacodynamic properties from BTZ may partially address the issue of inherent resistance, with increased response rates noted in some diseases. In addition, upstream UPS components, e.g., E3 ligases or deubiquitinating enzymes, may also be targetable in MCL.     

Acalabrutinib for adults with mantle cell lymphoma

Introduction: Although advances in mantle cell lymphoma (MCL) therapy have improved overall survival (OS), managing relapsed/refractory (R/R) cases remains a great challenge. Bruton tyrosine kinase (BTK) inhibitors have broadened therapeutic options in MCL and became the backbone of second-line strategies.

Areas covered: Ibrutinib, the first-in-class BTK inhibitor registered for MCL therapy, is efficient, with clear benefits of its use. However, ibrutinib-related adverse events due to off-target inhibition of other kinases led to the development of more selective molecules with comparable efficacy and better safety profiles.

Expert commentary: Acalabrutinib, a new BTK inhibitor, currently being evaluated in numerous clinical studies is approved by FDA in relapsing/refractory MCL. Its role will evolve over the next few years. Efficacy and good tolerability of acalabrutinib gives even greater opportunity for potential upfront use and new therapeutic combinations, including monoclonal antibodies, antibody-drug conjugates, immune checkpoint inhibitors, bcl-2 (B-cell lymphoma-2) or IP3K (phosphoinositide 3-kinase) inhibitors.     

Novel therapeutic targets in mantle cell lymphoma

Mantle cell lymphoma (MCL) is characterised by cell cycle dysregulation and a defective DNA damage response pathway. An evolving understanding of these processes has provided the rationale for development of novel agents targeting various steps that appear to be involved in lymphomagenesis and disease progression. Cyclin D1, overexpressed in nearly 100% of MCL, and the cyclin-dependent kinases were among the first rational targets identified. Therapies focusing on the PI3K/Akt pathway, the tumour microenvironment, and cell surface markers are also in various stages of exploration. Here, the authors discuss the rationale for developing targeted therapies and discuss future challenges in combining some of these agents.     

复发/难治性套细胞淋巴瘤治疗进展

套细胞淋巴瘤（MCL）是一种罕见的B细胞恶性肿瘤,占所有非霍奇金淋巴瘤（NHL）的3%~10%,常见于男性,中位发病年龄67岁,具有不可治愈、易复发和耐药等特点,复发后患者预后常较差,治疗选择有限。近年来,随着布鲁顿酪氨酸激酶抑制剂（BTKi）、B细胞淋巴瘤因子2抑制剂（BCL-2i）等为代表的靶向药物的应用,以及嵌合抗原受体T细胞（CAR-T）及异基因干细胞移植（allo-SCT）等疗法的进展,复发难治性（R/R）MCL患者的生存期明显延长。本文拟对目前R/R MCL的治疗进展进行综述。     

Present and future treatment options for primary CNS lymphoma

Introduction: Primary Central Nervous System (CNS) lymphomas are a rare group of malignancies with peculiar clinical and biologic features, aggressive course, and unsatisfactory outcome in contrast with other aggressive lymphomas. Despite a high chemo- and radiosensitivity, remissions are frequently short lasting, mainly because the blood–brain barrier limits the access of many drugs to the CNS, preventing a homogeneous treatment of all CNS tissues. Moreover, survivor patients are at high risk of developing severe treatment-related toxicity, mainly disabling neurotoxicity for elderly ones, raising the question of whether to intensify therapy to improve the cure rate or to downgrade treatment to reduce side effects. Although prognosis remains poor, it has significantly improved over the past two decades as a result of better treatment strategies with a curative aim.

Areas covered: The purpose of this review is to focus on either the actual pharmaco-therapeutic knowledge or the predictable future developments for the immunocompetent population (the vast majority of patients today). The most important published reports on these fields are presented.

Expert opinion: Actual front-line therapy consists of high-dose-methotrexate-based polichemotherapy, mostly in combination with high-dose cytarabine and/or alkylating agents. The use of high-dose chemotherapy supported by autologous stem-cell transplantation is increased; with some pros and cons, this strategy appears in controlling microscopic disease. Management of intraocular and meningeal lymphomas is controversial considering their peculiar characteristics that need to be specifically addressed. Finally, management of elderly patients and of relapsed disease is addressed.     

27 例套细胞淋巴瘤的临床特征及预后分析

目的 探讨套细胞淋巴瘤（MCL）的临床特征、化疗方案的疗效及预后情况。 方法 回顾性分析 27 例 MCL 患者资料, 分析其临床特征及治疗方案, 采用 Cox 回归分析 MCL 预后的影响因素。 结果 27 例患者中位发病年龄为 68 岁, 男女比例为 4.4∶ 1, Ann Arbor 分期Ⅲ～ Ⅳ者 25 例（92.6%）, 肝脾肿大者 8 例（29.6%）, 淋巴结外受累部位＞ 2 者 7 例（25.9%）、 ECOG 评分 2～ 4 分者 4 例（14.8%）, MIPI 评分 0～ 3 分者 8 例（29.6%）、 4～ 5 分者 14 例（51.9%）、6～ 11 分者 5 例（18.5%）, Ki-67≤30%者 9 例（33.3%）, ＞ 30%者 18 例（67.7%）, 有 B 症状者 10 例（37.0%）,乳酸脱氢酶（LDH）值升高者 17 例（63.0%）, β2-微球蛋白值升高者 8 例（29.6%）, 骨髓浸润者 7 例（25.9%）。 R-CHOP 方案组总有效率（ORR）为 81.8%, CHOP 方案组 ORR 为 68.8%。 多因素分析示年龄、LDH、Ki-67 为影响 MCL 预后的独立因素（P＜ 0.05）。 结论 MCL 以晚期多见, 年龄＞ 60 岁、LDH 值升高、Ki-67＞ 30%的患者预后不佳。     

自体干细胞移植治疗T细胞淋巴瘤31例临床分析

目的探讨自体干细胞移植治疗T细胞淋巴瘤的疗效和预后因素。方法回顾性分析了2004年5月—2009年12月我院的31例自体干细胞移植的T细胞淋巴瘤的临床资料,观察3年总生存率(OS)和无进展生存率(PFS),分析一般状况(PS)、乳酸脱氢酶(LDH)、移植前状况、分期、外周T细胞淋巴瘤(PTCL)预后指数(PIT)评分对生存的影响。结果中位随访时间为28(5~68)个月,1例患者死于严重肺部感染例(3.2%),12例复发(38.7%),3年PFS和OS分别为(56.7±1.2)%和(61.4±1.1)%。单因素分析结果示:移植前未达CR和PS>2与不良的预后相关(P<0.05)。多因素分析移植前未达CR是影响生存的独立危险因素(P<0.05)。结论自体干细胞移植治疗T细胞淋巴瘤是安全和有效的,移植前未达到CR是影响T细胞淋巴瘤患者自体干细胞移植生存期的独立危险因素。     

Targeting the B cell receptor pathway in non-Hodgkin lymphoma

Introduction: Dysregulated B cell receptor (BCR) signaling has been identified as a potent contributor to tumor survival in B cell non-Hodgkin lymphomas (NHLs). This pathway’s emergence as a rational therapeutic target in NHL led to development of BCR-directed agents, including inhibitors of Bruton’s tyrosine kinase (BTK), spleen tyrosine kinase (SYK), and phosphatidylinositol 3 kinase (PI3K). Several drugs have become valuable assets in the anti-lymphoma armamentarium.

Areas covered: We provide an overview of the BCR pathway, its dysregulation in B cell NHL, and the drugs developed to target BCR signaling in lymphoma. Mechanisms, pharmacokinetics, pharmacodynamics, efficacy, and toxicity of currently available BTK, SYK, and PI3K inhibitors are described.

Expert opinion: While the excellent response rates and favorable toxicity profile of the BTK inhibitor ibrutinib in certain NHL subtypes have propelled it to consideration as frontline therapy in selected populations, additional data and clinical studies are needed before other agents targeting BCR signaling influence clinical practice similarly. PI3K inhibitors remain an option for some relapsed indolent lymphomas and chronic lymphocytic leukemia, but their widespread use may be limited by adverse effects. Future research should include efforts to overcome resistance to BTK inhibitors, combination therapy using BCR-targeted agents, and exploration of novel agents.     

Treatment options of AIDS-related lymphoma

Recently, the median survival of patients with AIDS-related lymphoma has changed significantly. This effect is mainly because of changes in the use of antiviral (highly active antiretroviral therapy; HAART) or chemotherapy regimens. Several novel treatment options have been explored in patients with lymphoma. It is hoped that innovative strategies will lead to a survival benefit in these patients. In this review, we present an update of current strategies for the treatment of AIDS-related lymphoma.     

眼睑套细胞淋巴瘤临床病理分析

目的探讨眼睑原发性套细胞淋巴瘤（mantlecelllymphoma,MCL）的临床病理学特点及免疫表型。方法应用影像学及组织病理学技术对1例眼睑原发性MCL进行研究,观察其影像学特征、病理组织学形态及免疫组化表型。结果MRI提示右眼眶下缘片状等T1等T2信号影,边界清楚,大小约2．4cm×0．9cm×0．6cm,增强扫描轻度均匀强化,肿物邻近眼球,眼外肌结构完整,未见明确骨质破坏;光镜示肿瘤细胞弥漫性增生,肿瘤细胞小至中等大,核型不规则,染色质中度稀疏,可见核分裂像;肿瘤组织中散在分布上皮样组织细胞以及玻璃样变性红染的血管壁。免疫组化示：CD20（＋）,CD3（-）,CD5（＋）,CyclinD1（＋）。结论原发于眼睑部位的MCL非常罕见,影像学无特征性的表现,组织学形态表现独特,免疫组化标记有助于该病的诊断。     

Treatment strategies for relapsed and refractory aggressive non-Hodgkin's lymphoma

The aggressive non-Hodgkin's lymphomas (NHL) are a clinically heterogeneous group of lymphomas with disparate responses to standard chemotherapy regimens. Aggressive NHL includes diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and peripheral T-cell lymphomas (PTCL), among others. Significant advances have been made in the last decade in the initial treatment of DLBCL and MCL, but the treatment of relapsed or refractory disease remains difficult. The addition of rituximab to the treatment of DLBCL and MCL has improved clinical outcomes and is now a critical component of initial therapy and treatment of relapsed disease. The PTCLs, not having a similar agent to significantly change the treatment approach to these diseases, remain a difficult therapeutic problem. This review examines recent advances in the treatment of relapsed or refractory aggressive NHL and discusses novel approaches currently under investigation.     

NVP-BEZ235 alone and in combination in mantle cell lymphoma: an effective therapeutic strategy

Objectives: Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma; the complete response rate for standard therapies in use today is 85 – 90%. NVP-BEZ235 inhibits the PI3K/Akt/mTOR signaling axis at the level of both PI3K and mTOR. In this study, we analyzed the inhibitory effects of NVP-BEZ235 on mantle cell lines and its effects in combination with enzastaurin, everolimus and perifosine.

Methods: The effects of NVP-BEZ235 on cell proliferation and apoptosis were evaluated using MTT assay and flow cytometry analysis. The cell cycle analysis was performed applying BrdU incorporation. Western blot analysis was utilized for phosphorylation status evaluation of protein kinases. The interaction between NVP-BEZ235 and enzastaurin, everolimus and perifosine was examined by Chou-Talalay method.

Results: NVP-BEZ235 induced significant increase of apoptosis, both via intrinsic and extrinsic pathways. We found that NVP-BEZ235 inhibited mantle cells growth by induction of G1 arrest. NVP-BEZ235 exerts its antitumor activity even when mantle cells were in contact with bone marrow microenvironment. Enzastaurin, everolimus and perifosine enhanced the cytotoxicity triggered by NVP-BEZ235.

Conclusions: The above results encourage clinical development of NVP-BEZ235 in combination and the possible inclusion of patients with mantle lymphoma in Phase I/II clinical trials.     

Lenalidomide for the treatment of mantle cell lymphoma

Introduction: Although a variety of therapeutic schemes for Mantle Cell Lymphoma (MCL) have been attempted, the clinical outcome of patients continues to be unsatisfactory especially among patients with a very high-risk profile and in the relapsed/refractory setting. For this reason, recent clinical trials have explored novel approaches, either by the use of biological agents in chemotherapy-free schedules or by integrating them with chemoimmunotherapy regimens.

Areas covered: The efficacy of lenalidomide monotherapy and combination therapy established in clinical studies mainly involving relapsed/refractory MCL is reviewed. The mechanism of action of lenalidomide is also discussed. Furthermore, the current position of lenalidomide in the MCL treatment algorithm is debated.

Expert opinion: Lenalidomide demonstrated high efficacy and tolerability in several clinical trials as well as in retrospective real-world reports, even in patients who relapsed or were resistant to bortezomib and ibrutinib. In 2013, lenalidomide was approved by the Food and Drug Administration (FDA) for relapsed/refractory MCL after two prior therapies including at least one prior treatment with bortezomib. However, the potential synergistic anti-neoplastic effects of lenalidomide in combination with other biological agents, i.e. ibrutinib and venetoclax, especially in the management of p53-mutated cases, still remain an open issue.     

外周T细胞淋巴瘤诊治进展

外周T细胞淋巴瘤是国内比较常见的非霍奇金淋巴瘤类型之一,近年来随着基因表达谱等分子生物学方法在淋巴瘤研究中日益广泛的应用,人们对外周T细胞淋巴瘤的发病机制与预后分型的认识也逐渐加深。造血干细胞移植及抗肿瘤新药在临床的普遍应用也大大提高了该类病人的临床疗效与预后。     

利妥昔单抗联合自体外周血干细胞移植治疗非霍奇金淋巴瘤

目的：探讨利妥昔单抗联合自体外周血干细胞移植(autologous peripheral blood stem cell transplan- tation,APBSCT)治疗CD20阳性非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL)的可行性和有效性。方法：对4例CD20阳性NHL病人进行了5次利妥昔单抗联合APBSCT的治疗。利妥昔单抗于使用动员药物的前2 d使用,375 mg·m~(-2)静脉注射1次,观察病人使用利妥昔单抗的不良反应、动员效果及移植后的造血重建、并发症、临床转归。结果：所有病人均对利妥昔单抗耐受良好,动员后可采得足量CD34~+细胞,植入后在8～11 d内达造血重建,粒缺期出现短暂低热,无出血表现。移植后所有病人已随访5～44 mo。结论：利妥昔单抗联合APBSCT治疗CD20阳性NHL是一种耐受良好及效果良好的方法。     

50例套细胞淋巴瘤临床特征与预后的回顾性分析

目的 分析和探讨套细胞淋巴瘤(MCL)的临床特点、免疫表型与预后的影响因素.方法 回顾性分析50例MCL病人的临床资料、临床特征、生物学指标及治疗方案对总有效率(ORR)、无进展生存时间(PFS)、总生存期(OS)的影响.结果 50例MCL病人中位发病年龄62岁,男女比例3.5∶1,Ann-Arbor 分期Ⅲ~Ⅳ期病人为41例(82.0%).骨髓累及者19例(38.0%),消化道侵犯者11例(22.0%).50例病人中位生存期为61.0个月,中位无进展生存期为33.0个月.46例病人接受化疗,其中有18例病人使用化疗加利妥昔单抗;接受含与不含利妥昔单抗化疗的预期总生存期分别为74.0个月及46.5个月,差异无统计学意义(P=0.456).全组2、3、5年生存率分别为81.3%、72.0%、54.5%,2、3年无进展生存率分别为57.8%、46.7%.白细胞计数(WBC)与乳酸脱氢酶(LDH)水平高于正常、Ki-67≥30%、CD5(+)、MUM-1(-)均提示预后不良.多因素生存分析结果仅显示LDH水平(P=0.039),Ki-67≥30%(P=0.001)对MCL的预后差异有统计学意义,为MCL病人长期生存的独立影响因素.结论 MCL多发于老年男性,临床生物学行为具有侵袭性,常结外侵犯.治疗完全缓解率低,无疾病进展时间短,预后不佳.WBC与LDH高于正常、Ki-67≥30%、CD5(+)、MUM-1(-)是预后不良因素.LDH水平、Ki-67≥30%为MCL病人长期生存的独立影响因素.     

Treatment options for lysosomal storage disorders: developing insights

Introduction: Lysosomal storage disorders (LSDs) are clinically heterogeneous disorders that result primarily from lysosomal accumulation of macromolecules in various tissues. LSDs are always progressive, and often lead to severe symptoms and premature death. The identification of the underlying genetic and enzymatic defects has prompted the development of various treatment options.

Areas covered: To describe the current treatment options for LSDs, the authors provide a focused overview of their pathophysiology. They discuss the current applications and challenges of enzyme-replacement therapy, stem-cell therapy, gene therapy, chaperone therapy and substrate-reduction therapy, as well as future therapeutic prospects.

Expert opinion: Over recent decades, considerable progress has been made in the treatment of LSDs and in the outcome of patients. None of the current options are completely curative yet. They are complicated by the difficulty in efficiently targeting all affected tissues (particularly the central nervous system), in reaching sufficiently high enzyme levels in the target tissues, and by their high costs. The pathways leading from the genetic mutation to the clinical symptoms should be further elucidated, as they might prompt the development of new and ultimately curative therapies.     

自体外周血造血干细胞移植联合大剂量化疗治疗套细胞淋巴瘤的临床观察

目的探讨自体外周血造血干细胞移植（ASCT）联合大剂量化疗治疗套细胞淋巴瘤的临床疗效及安全性。方法总结2000年1月-2011年1月进行的自体外周造血干细胞移植联合大剂量化疗的28例套细胞淋巴瘤患者（移植组）的临床资料,并与同期28例接受常规治疗的套细胞淋巴瘤患者（常规化疗组）进行比较。结果移植组CR为67.9%,PR为32.1%,常规化疗组CR为57.1%,PR为42.9%,两组总有效率比较,差异无统计学意义（P〉0.05）;移植组5年OS（65%）显著高于常规化疗组（42%）,5年DFS（53%）亦高于常规化疗组（34%）,差异均有统计学意义（P〈0.05）。移植组Ⅳ度骨髓抑制的发生率（100%）明显高于常规化疗组（17.9%）,差异有统计学意义（P〈0.05）。结论 ASCT支持下大剂量化疗治疗套细胞淋巴瘤的临床疗效好于常规化疗,且安全性较高。     

Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma

Auroras (A and B) are oncogenic serine/threonine kinases that play key roles in the mitotic phase of the eukaryotic cell cycle. Analysis of the leukemia lymphoma molecular profiling project (LLMPP) database indicates Aurora over-expression correlates with poor prognosis. A tissue microarray (TMA) composed of 20 paired mantle cell lymphoma (MCL) patients demonstrated >75% of patients had high levels Aurora expression. Aurora A and B were also found elevated in 13 aggressive B-NHL cell lines. MLN8237, an Aurora inhibitor induced G2/M arrest with polyploidy and abrogated Aurora A and histone-H3 phosphorylation. MLN8237 inhibited aggressive B-NHL cell proliferation at an IC₅₀ of 10–50 nM and induced apoptosis in a dose- and time-dependent manner. Low dose combinations of MLN8237 + docetaxel enhanced apoptosis by ∼3–4-fold in cell culture compared to single agents respectively. A mouse xenograft model of MCL demonstrated that MLN8237 (10 or 30 mg/kg) or docetaxel (10 mg/kg) alone had modest anti-tumor activity. However, MLN8237 plus docetaxel demonstrated a statistically significant tumor growth inhibition and enhanced survival compared to single agent therapy. Together, our results suggest that MLN8237 plus docetaxel may represent a novel therapeutic strategy that could be evaluated in early phase trials in relapsed/refractory aggressive B-cell NHL.