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.     

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.     

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。     

VcR-CAP方案治疗初治性套细胞淋巴瘤138例

目的研究Vc R-CAP方案(硼替佐米+利妥昔单抗+环磷酰胺+多柔比星+泼尼松)治疗初治性套细胞淋巴瘤(MCL)的临床疗效及不良反应。方法初治性MCL患者138例,根据套细胞淋巴瘤国际预后指数(MIPI)评分分为低危组、中危组和高危组。给予Vc R-CAP方案治疗,每疗程21 d,利妥昔单抗375 mg·m~(-2)(第1日),环磷酰胺750 mg·m~(-2)(第1日),多柔比星50 mg·m~(-2)(第1日),泼尼松100 mg·m~(-2)(第1~5日),硼替佐米1.3 mg·m~(-2)(第1、4、8、11日),共6个疗程。评价临床疗效,进行临床特征与生存分析,观察不良反应。结果低危组总有效率为70%(47/67),中危组为50%(21/42),高危组为34%(10/29)。年龄≥60岁、Ann Arbor分期Ⅲ~Ⅳ期、出现侵袭及乳酸脱氢酶升高的患者无进展生存期和总生存期较年龄<60岁、Ann Arbor分期Ⅰ~Ⅱ期、无侵袭及乳酸脱氢酶正常的患者短,低危组、中危组、高危组的生存期存在显著差异(均P<0.05)。化疗引起的不良反应以贫血、血小板减少、中性粒细胞减少、恶心/呕吐为主,程度以1~2级为主,未影响治疗进展。结论 Vc R-CAP方案对初治性MCL患者安全有效。     

Current management of mantle cell lymphoma

Mantle cell lymphoma is a rare yet well defined subtype of B-cell non-Hodgkin's lymphoma. The correct histological diagnosis of this lymphoma subtype is of the utmost importance; however, it is also a very difficult diagnosis. Clinical management is often complex, and despite the successful introduction of monoclonal antibodies and dose-intensified regimens, including autologous and allogeneic stem cell transplantation strategies, the prognosis remains particularly poor. Recently gained insights into the underlying biology and pathogenesis have unravelled numerous promising molecular targeting strategies; however, their introduction into clinical practice and current treatment algorithms remains a challenge. This article addresses these issues providing relevant information for current state-of-the-art management of patients with mantle cell lymphoma and giving a perspective of upcoming treatment strategies.     

Treatment options for mantle cell lymphoma

Introduction: In this article, we provide an accurate overview of both standard treatment option and novel promising therapeutics. Major impact is on novel agents now being tested in randomized clinical trials. While the initial data are promising, they may rapidly expand treatment options, change existing paradigms and further improve outcomes for mantle cell lymphoma (MCL) patients.

Areas covered: MCL is a disease with indolent histology, but aggressive clinical course. However, for now, MCL remains incurable and the search for the most effective and tumor-specific treatment still represents a great challenge for oncohematologists. However, the implementation of chemotherapy together with the anti-CD20 antibody rituximab, as well as the growing use of autologous stem cell transplantation in first remission, have improved effects of treatment in MCL, including even some improvement in overall survival. Recently, treatment modalities for MCL have been expanded by strategies based on several biologically targeted agents, including m-TOR kinase or proteasome inhibitors and immunomodulatory agents, such as lenalidomide. B-cell receptor pathway inhibitors, such as ibrutinib and idelalisib, and histone deacetylase or cyclin-dependent kinase inhibitors have also shown promising activity in resistant or relapsed disease.

Expert opinion: Although enormous progress was made in the treatment of MCL over the last year, the disease remains incurable. One chance for the significant life prolongation is intensive treatment with consolidative auto SCT. However, real progress may be afforded by developing the novel agents described in this article. In this way, MCL may soon become another potentially curable oncological malignancy.     

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.     

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.     

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.     

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.     

Current status of targeted therapies for mantle cell lymphoma

Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma (NHL) with treatment outcomes that have historically been poorer than those observed with other NHL subtypes. Patients typically present with advanced-stage disease and frequent extranodal involvement; the median age at diagnosis is >60 years. Recent improvements in progression-free and overall survival have been observed with more dose-intensive strategies, although at least half of patients diagnosed with MCL are not eligible for such treatment approaches based on age and co-morbidities. In addition, therapy options for relapsed MCL are limited. Only bortezomib is approved for treatment of relapsed MCL in the US. Development of targeted therapy approaches to minimize toxicities while preserving anti-neoplastic properties is of particular importance in MCL. Multiple ongoing studies are attempting to build on the known efficacy of bortezomib by evaluating combination regimens with other targeted agents or cytotoxic chemotherapy. The mammalian target of rapamycin (mTOR) inhibitor temsirolimus has known activity in MCL, making this an attractive class of agents for further investigation in combination regimens. Rituximab and other monoclonal antibodies are being evaluated for novel roles in MCL treatment, including as maintenance therapy. Other classes of drugs being investigated in MCL are immunomodulatory agents, inhibitors of the phosphoinositide 3-kinase/Akt and B-cell receptor signalling pathways, and inhibitors of bcl-2 and histone deacetylase. Although many of the agents appear to have modest single-agent activity, the favourable toxicity profile of many agents will make them best suited for incorporation into combination regimens.     

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。     

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。     

Temsirolimus and mantle cell lymphoma. Highly toxic, limited efficacy

Mantle cell lymphoma is a highly malignant non-Hodgkin's lymphoma. There is no consensus on chemotherapy regimens for patients who do not qualify for haematopoietic stem cell transplantation. Temsirolimus, a metabolic precursor of sirolimus, already marketed in the European Union for metastatic kidney cancer, recently received an extension of indications to include relapsed or refractory mantle cell lymphoma. In this setting, one trial involving 162 patients in whom 2 or 3 chemotherapy regimens had failed compared two doses of temsirolimus (175 mg per week for 3 weeks, followed by 75 mg or 25 mg per week) versus a control group receiving various other treatments. The median overall survival time was about 11 months, regardless of the treatment.The median survival time before radiological or clinical progression was slightly longer with the higher dose of temsirolimus than in the control group (4.8 versus 1.9 months). Both of the temsirolimus dose regimens were highly toxic: 5 deaths, haematological disorders in more than 90% of patients, and haemorrhage or severe thrombocytopenia in about 50% of cases. Reactions during the infusion, infections, mucositis, fatigue and diarrhoea were also frequent.The cytochrome P450 isoenzyme CYP 3A4 is involved in temsirolimus metabolism, hence a high risk of pharmacokinetic interactions. The packaging is inappropriate and represents a potential source of dosing errors. In practice, temsirolimus shows only limited efficacy but is highly toxic in patients with relapsed or refractory mantle cell lymphoma after several prior chemotherapy regimens. It is better to avoid using this drug.     

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.     

利妥昔单抗联合CHOP方案治疗弥漫大B细胞性淋巴瘤的多中心临床研究

目的:观察利妥昔单抗联合环磷酰胺、长春新碱、多柔比星及泼尼松(CHOP方案)治疗新诊断的弥漫性大B细胞性淋巴瘤(DLBL)的临床疗效. 方法:2002年4月至2003年2月,共52例病人进入本研究.化疗采用标准的CHOP方案:d 1,环磷酰胺600 mg·m-2,长春新碱1.4 mg·m-2,多柔比星25 mg·m-2,泼尼松60 mg·m-2×5 d,每3 wk一个疗程,共6个疗程.利妥昔单抗静脉滴注剂量为375 mg·m-2,于化疗第一个疗程前2 d开始,每周输注1次(连续输注),连续4次(标准剂量)或6次(增强剂量);或于每疗程的CHOP方案化疗前2 d输注,每3周1次(间隔输注),输注4次(标准剂量)或6次(增强剂量).结果:50例病人进入临床疗效评估, 60 %获得完全缓解,总有效率为 100 %.其中,34例Ann Arbor分期为Ⅲ期或Ⅳ期的病人有15例获得完全缓解,完全缓解率为44 %.50例病人共随访了(8±s 5) wk, 2～30 wk,病人16 wk的无病生存(PFS)率为87 %.标准剂量组和增强剂量组疗效无显著差异,连续输注和间隔输注疗效差异亦无显著意义(P>0.05).所有病人在治疗过程中对本方案均能较好耐受,主要的不良反应为输注相关的不良反应(32 %)和化疗相关的血液学不良反应(20 %). 结论:利妥昔单抗联合CHOP方案可有效用于治疗新诊断的弥漫性大B细胞性淋巴瘤,它具有较高的完全缓解率,而且在治疗中不良反应较小.