硼替佐米联合阿霉素及地塞米松治疗复发难治性套细胞淋巴瘤15例

探讨硼替佐米联合阿霉素、地塞米松组成的PAD（bortezomib、doxorubicin and dexamethasone）方案治疗复发、难治性套细胞淋巴瘤（mantle cell lymphoma,MCL）的疗效及安全性。方法：用PAD方案治疗15例复发、难治性MCL,分析其疗效及影响因素,同时观察不良反应。PAD方案治疗4～6个疗程：硼替佐米（1.3 mg/m2,d1、4、8、11,快速静脉注射）、阿霉素（10 mg/d,d4～6,静脉注射）和地塞米松（40 mg/d,d4～6,口服,每21天为1个疗程）。结果：80%（12/15）患者达PR及PR以上疗效,其中CR 26.7%（4/15,均经PET-CT证实）,PR 53.3%（8/15）。无病进展时间（PFS）13.5（3.5～25.1）个月,中位生存时间（OS）35.6（6.3～42.8）个月。PAD方案主要不良反应表现为：Ⅲ～Ⅳ级血小板减少（33.3%）,Ⅱ级乏力（26.7%）,Ⅱ级周围神经炎（13.3%）,带状疱疹病毒感染（20.0%）。结论：PAD方案可有效提高难治性MCL患者疗效,不良反应多轻微可控。     

Rituximab-induced acute thrombocytopenia: a case report and review of the literature

Rituximab is a chimeric monoclonal antibody directed against the phosphoprotein CD20. Because of its efficacy and acceptable toxicity profile, rituximab is now commonly used for the treatment of CD20-positive B-cell malignancies, including B-cell non-Hodgkin’s lymphoma. However, rituximab-induced acute thrombocytopenia is an extremely rare side effect. We report a case of acute thrombocytopenia occurring immediately after rituximab infusion in a mantle cell lymphoma patient with bone marrow involvement and massive splenomegaly. Although the mechanism of thrombocytopenia is still unclear, it is possible that tumor burden, bone marrow involvement, the presence of infusion-related symptoms, and mantle cell histology are related to this rare complication of rituximab therapy. Hence, rituximab should be used with caution in patients who have these factors, and clinicians must be aware of this rare, but serious, side effect.     

SOHO State of the Art Updates and Next Questions: Tailoring Upfront Therapy in Mantle Cell Lymphoma

In this article, we will review current strategies for the front-line management of mantle cell lymphoma, an uncommon and biologically and clinically heterogeneous subtype of non-Hodgkin lymphoma that remains incurable with current therapies. Patients invariably relapse with time, and as a result, treatment strategies involve persistent therapy over the course of months to years, including induction, consolidation, and maintenance. Topics discussed include the historical development of various chemoimmunotherapy backbones with continued modifications to maintain and improve efficacy while limiting off-target, off-tumor effects. Chemotherapy-free induction regimens were developed initially for elderly or less fit patients though are now being utilized for younger, transplant-eligible patients due to deeper, more prolonged remission durations with fewer toxicities. The historic paradigm of recommending autologous hematopoietic cell transplant for fit patients in complete or partial remission is now being challenged based in part on ongoing clinical trials in which minimal residual disease directed approaches influence the consolidation strategy for any particular individual. The addition of novel agents, namely first and second generation Bruton tyrosine kinase inhibitors as well as immunomodulatory drugs, BH3 mimetics, and type II glycoengineered anti-CD20 monoclonal antibodies have been tested in various combinations with or without immunochemotherapy. We will attempt to help the reader by systematically explaining and simplifying the various approaches for treating this complicated group of disorders.     

套细胞淋巴瘤的临床病理分析合并文献复习

目的：探讨套细胞淋巴瘤的组织学特征及免疫组化特点。方法对4例套细胞淋巴瘤的临床资料、病理形态学进行分析,并结合文献对其诊断及鉴别诊断进行探讨。结果套细胞淋巴瘤3例,男女比例为1：3,年龄44-69岁,平均年龄57岁,套细胞淋巴瘤免疫分型均为B淋巴细胞型,并伴有细胞周期D1的高度表达。结论套细胞淋巴瘤,发生率比较低,预后较差,细胞学形态特征及免疫组化特点对套细胞淋巴瘤的诊断具有重要价值。     

Long-Term Follow-Up of R-CHOP With Bevacizumab as Initial Therapy for Mantle Cell Lymphoma: Clinical and Correlative Results

BackgroundEmerging evidence indicates that MCL has increased angiogenesis within the tumor microenvironment. We initiated a phase II trial to determine if the addition of bevacizumab to the standard R-CHOP regimen could enhance antitumor effects in patients with previously untreated MCL.Patients and MethodsEleven patients with previously untreated MCL received bevacizumab at 15 mg/kg on day 1, and standard CHOP-21 (CHOP given every 21 days per cycle) with rituximab (375 mg/m² per cycle) on day 3 of each cycle for a total of 6 cycles. Planned study end points included safety and efficacy assessment, and exploratory analysis of angiogenic profiles. The study was suspended in August of 2010 based on safety findings in DLBCL (diffuse large B-cell lymphoma) of increased cardiovascular events with the regimen.ResultsBeyond the standard R-CHOP safety profile, Grade 3 left ventricular dysfunction developed in 2 patients (18%), Grade 1/2 hypertension, proteinuria, and bleeding each developed in 1 patient (9%). The overall response rate was 82% with 36% complete response (CR)/complete response unconfirmed (CRu). The median progression-free survival (n = 11) was 18 months (95% confidence interval, 3-not reached), and 3-year overall survival rate was 82%. Correlative studies showed increased vascular endothelial growth factor receptor 1 expression in tumor cells at baseline, and elevated levels of plasma vascular endothelial growth factor (VEGF) throughout treatment.ConclusionThe addition of bevacizumab to the standard R-CHOP regimen did not appear to significantly improve efficacy beyond that observed from previous studies using R-CHOP alone. Therapeutic strategies that provide sustained inhibition on VEGF-related and VEGF-independent targets within the tumor microenvironment might further improve antiangiogenic effects and warrant further exploration in MCL.     

Carfilzomib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma: A Phase I Trial

IntroductionWe designed a multicenter, phase Ib dose-escalation trial of carfilzomib with bendamustine and rituximab in patients with relapsed/refractory non-Hodgkin lymphoma (NCT02187133) in order to improve the response rates of this difficult-to-treat population. Chemoimmunotherapy with bendamustine and rituximab has shown activity in a variety of lymphomas, and proteasome inhibitors have demonstrated pre-clinical synergy and early clinical activity in this population. The objectives were to determine the maximum tolerated dose of carfilzomib and the preliminary efficacy of this combination.Patients and MethodsThe protocol followed a 3+3 design of carfilzomib dose escalation combined with standard doses of bendamustine and rituximab. Patients were treated for up to 6 cycles with an interim positron emission tomography/computed tomography after cycle 3.ResultsTen patients were treated on the dose-escalation phase. The study was terminated at a carfilzomib dose of 56 mg/m², and the maximum tolerated dose was not reached. The most common grade 3/4 adverse event was thrombocytopenia. There was 1 dose-limiting toxicity observed, grade 3 febrile neutropenia, and there were no treatment-related deaths. The overall response rate was 40% (complete response rate, 30%), with a median duration of response of 12 months and a median progression-free survival of 2.1 months.ConclusionCarfilzomib in combination with bendamustine and rituximab is a safe and well-tolerated treatment for patients with relapsed/refractory non-Hodgkin lymphoma. Preliminary data indicate that this combination may have efficacy with an acceptable side effect profile in this heavily pre-treated patient population with limited treatment options.     

Network Analysis of microRNAs,Genes and their Regulation in Mantle Cell Lymphoma

The pathogenesis of mantle cell lymphoma, a special subtype of lymphoma that is invasive and indolent andhas a median survival of 3 to 4 years, is still partially unexplained. Much research about genes and miRNAshas been conducted in recent years, but interactions and regulatory relations of genetic elements which mayplay a vital role in genesis of MCL have attracted only limited attention. The present study concentrated onregulatory relations about genes and miRNAs contributing to MCL pathogenesis. Numerous experimentallyvalidated raw data were organized into three topology networks, comprising differentially expressed, associatedand global examples. Comparison of similarities and dissimilarities of the three regulating networks, pairedwith the analysis of the interactions between pairs of elements in every network, revealed that the differentiallyexpressed network illuminated the carcinogenicity mechanism of MCL and the related network further describedthe regulatory relations involved, including prevention, diagnosis, development and therapy. Three kinds ofregulatory relations for host genes including miRNAs, miRNAs targeting genes and genes regulating miRNAswere concluded macroscopically. Regulation of the differentially expressed miRNAs was also analyzed, in termsof abnormal gene expression affecting the MCL pathogenesis. Special regulatory relations were uncovered. Forexample, auto-regulatory loops were found in the three topology networks, key pathways of the nodes beinghighlighted. The present study focused on a novel point of view revealing important influencing factors for MCLpathogenesis.