Lenalidomide for the treatment of B-cell lymphoma

Introduction: Although the combination of an anti-CD20 monoclonal antibody and chemotherapy has widely improved survival of patients with B-cell lymphoma, the disease still relapses. A better understanding of the biology of lymphomas has highlighted the role of the cell of origin in response to treatment and outcome. Lenalidomide represents an attractive therapeutic option due to its original mechanism of action.

Areas covered: In this review, the authors describe the pharmacological properties of lenalidomide, and the rational for its use in B-cell lymphomas; focusing on diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). They discuss the mechanism of action of the drug and its current and future clinical development. They also review the current data in relapsed/refractory situations as well as in first-line treatment.

Expert opinion: Lenalidomide is an oral non-chemotherapy immunomodulatory agent with an acceptable toxicity profile and manageable side-effects. Efficacy has widely been demonstrated, especially in MCL, FL and non-Germinal Center DLBCL patients. Further studies are now warranted to better define the strategy for the use of lenalidomide in B-NHL patients, and clarify which subgroup of patients will really benefit of lenalidomide as part of first-line treatment or in a relapsed/refractory setting.     

Cost-effectiveness analysis of the addition of rituximab to CHOP in young patients with good-prognosis diffuse large-B-cell lymphoma

BACKGROUND and objective: Diffuse large-B-cell lymphoma (DLBCL) is an aggressive form of lymphoma. It accounts for 30-40% of all new cases of non-Hodgkin's lymphoma and is the subtype with the highest overall incidence. Before the development of monoclonal antibodies, the standard treatment of newly diagnosed DLBCL was based on combination therapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). Current treatment consists of the combination of CHOP and the monoclonal antibody rituximab (R-CHOP regimen), with recovery rates of 70%. The aim of this study was to compare the efficacy (survival) and direct medical costs of two chemotherapy regimens, R-CHOP and CHOP, in the treatment of DLBCL in young patients with a good prognosis. METHODS: A decision-analysis model with tree structure was used to compare R-CHOP and CHOP in the treatment of young patients with DLBCL from the perspective of the Italian National Health Service. Patients entered at the root of the tree and followed one of the six possible therapeutic pathways. After receiving one of the two chemotherapy treatments (R-CHOP or CHOP) for 5 months, patients could have a complete response or not. In the presence of no response, patients underwent rescue therapy. In the case of relapse after 3 years' follow-up (following an initial complete response at 5 months), patients were given rescue therapy. The model provided an estimate of mean survival (life-years gained [LYG]) and mean costs (direct medical costs) over a period of 3 years. Both survival and costs were discounted at a rate of 3%. Costs were in euro, year 2007 values. Several sensitivity analyses were carried out with varying clinical parameters. RESULTS: The LYG with the R-CHOP regimen was higher (2.697 LYG per patient) than with the CHOP regimen (2.517 LYG per patient). When taking into account the cost of rescue therapy, the overall mean treatment cost per patient was lower with the R-CHOP regimen (22,113.44 euro) than with the CHOP regimen (22,831.17 euro). Sensitivity analyses showed that the incremental cost-effectiveness ratios per LYG for complete response at 5 months (16,816.00 euro) and for relapse-free survival at 3 years (11,967.12 euro) were below the internationally accepted threshold (50,000 euro). Furthermore, for survival at 3 years, R-CHOP was confirmed as the dominant therapy (lower expected mean costs, higher number of LYG). CONCLUSIONS: Our study demonstrated the clinical and economic benefits of adding rituximab to a CHOP chemotherapy regimen in young patients who present with DLBCL with good prognosis. The higher costs associated with rituximab were offset by the significantly lower rescue therapy costs. Further studies that include patients with unfavourable prognosis are needed to confirm these findings.     

Newer developments in adult T-cell leukemia/lymphoma therapeutics

Introduction: Adult T-cell leukemia/lymphoma (ATL) is a rare disease with a unique geographic distribution. Conducting controlled randomized trials to assess the effective therapeutic strategies has therefore been a significant challenge to date.

Areas covered: This review explores the natural history and diagnostic evaluation of ATL, followed by a focused review of existing studies on the most potent individual pharmaceutical agents and combinations used in the therapy of this malignancy. Readers will acquire considerable insights about the clinical subsets, diagnosis and the most effective therapies used in various ATL types.

Expert opinion: International, multicenter, randomized clinical trials are essential to design optimal therapeutic strategies for various ATL subsets. It appears that patients with acute ATL type benefit considerably from the first-line combined antiviral therapy with zidovudine and interferon alpha, whereas patients with ATL of the lymphoma type may experience a better outcome with intensive chemotherapy. The role of therapy in smoldering and chronic disease types remains to be clarified. In addition, the results of allogeneic stem-cell transplantation in ATL appear promising, as up to 40% of patients who achieve remission and have suitable donors can now become long-term survivors. Prospective evaluation of novel effective agents and their incorporation into various therapeutic algorithms is stringently needed.     

弥漫大B细胞淋巴瘤临床病理特点及预后因素分析

目的分析弥漫大B细胞淋巴瘤（DLBCL）临床病理学特点及与预后的关系。方法回顾性分析114例DLBCL患者的临床资料,分析患者临床病理学特征与疗效之间的关系。结果国人DLBCL中非生发中心来源（non-GCB）亚型占70%;CHOP样方案可以获得64.9%的持续完全缓解率;患者治疗前的ECOG评分、血清LDH水平、B症状、大病灶以及血红蛋白水平具有预后意义（P〈0.05或〈0.01）。结论国人DLBCL以non-GCB亚型为主,ECOG评分、血清LDH水平、B症状、大病灶以及血红蛋白水平具有预后意义。     

Medical treatment of small cell lung cancer: state of the art and new development

Introduction: Small cell lung cancer (SCLC) is a rapidly progressive disease that accounts for approximately 15% of all lung cancers. Chemotherapy remains the cornerstone of treatment of SCLC, but in the last two decades, its progress has reached a plateau. Although a significant sensitivity to chemotherapy and radiotherapy is a feature of SCLC, an early development of drug resistance unavoidable occurs during the course of the disease. Second-line treatment for relapsed patients remains a very challenging setting, with a limited clinical benefit.

Areas covered: A thorough analysis of various therapeutic strategies reported in literature for SCLC treatment was performed. This review includes novel therapeutic approaches such as maintenance or consolidation treatments, new chemotherapy agents and targeted therapy.

Expert opinion: Against this background, there is a desperate need for the development of novel active drugs. Among these, amrubicin has also shown more favourable antitumor activity, and is the most promising at present. Concerning targeted agents, these have failed to demonstrate effectiveness for SCLC and a better understanding of the molecular mechanisms is clearly needed. In the future, further investigations are required to clarify the role of novel anti-angiogenic or pro-apoptotic agents and hedgehog pathway inhibitors.     

Brentuximab Vedotin (SGN-35), an antibody–drug conjugate for the treatment of CD30-positive malignancies

Introduction: CD30-positive hematological malignancies are potentially curable with frontline combination chemotherapy regimens; however, those patients who relapse or are refractory to initial therapies have less favorable prognosis.

Areas covered: Brentuximab vedotin is an antibody–drug conjugate (ADC) composed of the anti-CD30 chimeric IgG1 monoclonal antibody cAC10 and the potent antimicrotubule drug monomethylauristatin E connected by a protease-cleavable linker. Treatment with single-agent brentuximab vedotin resulted in unprecedented objective response rates and complete response rates of 75 and 34%, respectively, in relapsed or refractory Hodgkin lymphoma, and of 86 and 57%, respectively, in relapsed or refractory systemic anaplastic large-cell lymphoma patients. Peripheral sensory neuropathy and neutropenia were observed with brentuximab vedotin but were generally grade 1 and 2 in severity and manageable. In August 2011, brentuximab vedotin was approved in the US for the treatment of Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in ASCT-ineligible candidates, and for the treatment of systemic anaplastic large-cell lymphoma after failure of at least one prior multiagent chemotherapy regimen.

Expert opinion: These data support an expanded development program for brentuximab vedotin in multiple CD30-positive indications.     

Hodgkin's lymphoma therapy: past,present, and future

Importance of the field: The treatment of Hodgkin's lymphoma (HL) with the use of radiotherapy and systemic chemotherapy has been one of the success stories of modern oncology. HL therapy has been the paradigm for the systematic evaluation of different curative modalities, resulting in cure for the majority of patients. The current focus is on designing initial therapeutic strategies that retain efficacy and minimize long-term toxicity. Appropriate use of pathologic, clinical, biologic and radiologic prognostic factors in identification of aggressive HL is paramount in designing a successful therapeutic strategy.

Areas covered in this review: This review addresses the current and future use of prognostic tools, including PET scanning and other biomarkers, in identifying patients with aggressive HL, with reference to publications from the last two decades. The current standard approaches with the use of combined modality therapy and systemic chemotherapy as well as the promising role of future response-adapted strategies is reviewed.

What the reader will gain: The reader will obtain a comprehensive review of risk assessment strategies as well as current and investigational therapeutic approaches in the management of HL.

Take home message: In HL, appropriate utilization of risk assessment strategies is required to maximize therapeutic outcomes while minimizing toxicity, especially long-term toxicity. Response-adapted therapy utilizing PET has the potential to profoundly improve the therapeutic landscape in HL.     

弥漫性大B细胞淋巴瘤IL-6和VEGF表达水平与化疗耐药的相关性

目的探讨弥漫性大B细胞淋巴瘤(DLBCL)患者血清白细胞介素6(IL-6)、血管内皮生长因子(VEGF)的表达及与化疗耐药之间的相关性。方法采用酶联免疫吸附试验(ELISA)分别测定16例化疗耐药患者(化疗耐药组)、20例化疗敏感患者(化疗敏感组)治疗前后和15例健康者(对照组)血清IL-6、VEGF水平。结果化疗耐药组患者血清IL-6、VEGF初治前表达水平明显高于化疗敏感组患者初治前和对照组(P<0.05),治疗缓解后明显低于治疗前(P<0.05)。DLBCL复发耐药时,患者血清中的IL-6、VEGF又高于缓解时水平(P<0.05)。化疗耐药组Ⅲ～Ⅳ期患者治疗前、复发耐药时IL-6、VEGF水平明显高于Ⅰ～Ⅱ期患者(P<0.05)。结论 DLBCL患者血清IL-6、VEGF表达水平的变化,提示其可以作为观察DLBCL病情变化的检测指标,可能与DLBCL细胞耐药有关。     

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.     

Enzastaurin hydrochloride for lymphoma: reassessing the results of clinical trials in light of recent advances in the biology of B-cell malignancies

Introduction: The B-cell receptor (BCR) is critical for the development and persistence of B-cell non-Hodgkin lymphoma (B-NHL). Protein kinase C-beta (PKC-β) has been identified as one of the key signaling hubs downstream of the BCR and constitutes a valuable target in B-NHL. As a potent PKC-β inhibitor, enzastaurin is currently being tested in Phase II/III trials.

Areas covered: This review summarizes the latest results and ongoing clinical trials with enzastaurin in light of basic scientific advances in the understanding of various lymphoid cancers, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) and Waldenström's macroglobulinemia (WM).

Expert opinion: While its continued clinical development is uncertain, enzastaurin should be regarded as a stepping stone for the development of future therapies; indeed, the recent research has provided valuable insight into the possible molecular mechanisms that explain its limited clinical activity especially in the treatment of DLBCL and MCL. It should be noted that there is still some interest in enzastaurin, in combination, for the treatment of WM.     

Therapeutic targeting of EGFR in malignant gliomas

Importance of the field: Despite the improved prognosis for many cancer patients, the survival of those with malignant gliomas (MGs) remains dismal. Even with aggressive intervention, including surgery, chemotherapy and radiotherapy, the overall 2-year survival rate is only 25% in the most optimistic series, and 5-year survival rates are consistently in the low single digits. Therefore, it is evident that novel therapeutic paradigms are necessary to overcome the inherent limitations of conventional treatments. EGFR gene overexpression can be found in 40 – 50% of patients with MGs, whereas its expression is very low in normal brain. Therapeutic targeting of EGFR has indicated clinical success in the treatment of MGs.

Areas covered in this review: The purpose of this review is to discuss the current status of several EGFR-targeted therapies in MGs patients and address the efficacy of these drugs as monotherapy or in combination with other drugs and/or treatments. We also emphasize the lessons learned and the future perspectives in the development of EGFR-targeted therapies for MGs.

What the reader will gain: A more comprehensive understanding of the molecular, structural and biological characteristics of EGFR and the mechanisms of action of EGFR-targeted antagonists will most likely contribute to the successful use of strategies of EGFR-targeted therapy in the clinic.

Take home message: Therapeutic targeting of EGFR include anti-EGFR mAbs, small-molecule EGFR tyrosine kinase inhibitors, peptide vaccination therapy and other therapeutic strategies. Each EGFR antagonist has its own advantages and limitations in terms of BBB crossing, ease of delivery, combination therapies and potential toxicity. Therefore, a multiple approach combining different agents that target EGFR signaling at multiple levels seems to have potential as future therapeutics for MGs, once the technical and safety issues unique to each of the approaches are overcome.     

Ten years of rituximab in NHL

Background: Rituximab, a chimeric mouse/human monoclonal antibody targeting the pan-B-cell antigenic marker CD20, was the first monoclonal antibody licensed for use in the treatment of cancer. Objective: This review focuses on the impact of rituximab in the treatment of patients with B-cell non-Hodgkin lymphoma (NHL). Methods: Three key areas related to the use of rituximab in B-cell NHL are discussed: mechanism of action, clinical efficacy in both indolent and aggressive disease, and safety of its use as both monotherapy and in combination with chemotherapy. Results/conclusions: Rituximab has demonstrated significant clinical efficacy in the treatment of NHL, particularly in combination with chemotherapy, and its use has revolutionized the treatment of both indolent and aggressive B-cell NHL over the past decade. Furthermore, consistent toxicity data have been obtained with a safe and tolerable profile in most patients.     

Investigational therapies targeting CD37 for the treatment of B-cell lymphoid malignancies

Introduction: While chemotherapy still remains a cornerstone of oncologic therapy, immunotherapy with monoclonal antibodies has steadily improved the treatment strategy for several hematologic malignancies. New treatment options need to be developed for relapsed and refractory non-Hodgkin lymphoma (NHL) patients. Currently, novel agents targeting specific molecules on the surface of lymphoma cells, such as anti-CD37 antibodies, are under considerable investigation. Here we report on anti-CD37 targeting for the treatment of patients with B-cell NHL.

Areas covered: CD37 seems to be the perfect therapeutic target in patients with NHL. The CD37 antigen is abundantly expressed in B-cells, but is absent on normal stem cells and plasma cells. It is hoped that anti-CD37 monoclonal antibodies will increase the efficacy and reduce toxicity in patients with both newly diagnosed and relapsed and refractory disease. Recent clinical trials have shown promising outcomes for these agents, administered both as monotherapy and in combination with standard chemotherapeutics.

Expert opinion: The development of new therapeutic options might help to avoid cytotoxic chemotherapy entirely in some clinical settings. This article presents the latest state of the art on the new treatment strategies in NHL patients. It also discusses recently approved agents and available clinical trial data.     

Antibody therapy of lymphoma

The availability of rituximab and the possible imminent availability of two new radiolabelled monoclonal anti-CD20 antibodies (Yttrium-90 (⁹⁰Y)-ibritumomab and Iodine-131(¹³¹I)-tositumomab) have captured much attention in the treatment of lymphoma. The chimeric monoclonal anti-CD20 antibody, rituximab has truly heralded a new era for the treatment of lymphoma and human malignancies. The full potential of antibody-based therapy to improve the outcome in patients with B-cell non-Hodgkin’s lymphoma has yet to be defined, but recent data suggests that the combination of chemotherapy plus rituximab may significantly improve outcome for patients with aggressive lymphoma over chemotherapy alone. Highly promising data are also emerging for the use of rituximab in combination with chemotherapy in other types of lymphoma. New advances in antibody therapy, driven by new technologies and defining novel antigen targets, offer the promise of more effective tumour specific therapies. Combinations of antibodies, either conjugated with radioisotopes or unlabelled, used with chemotherapy are likely to provide definitive advances in the treatment of lymphoma in the immediate future.     

Emerging drugs for endometrial cancer

Introduction: From the dualistic classification that divides endometrial cancer (EC) into two types with distinct underlying molecular profiling, histopathology and clinical behavior, arises a deeper understanding of the carcinogenesis pathways. EC treatment comprises different and multimodal therapeutic approaches, such as chemotherapy, radiation therapy or combinations of novel drugs; however, few of these regimens have truly improved progression-free or survival rates in advanced and metastatic settings.

Areas covered: We reviewed the main molecular pathways involved in EC carcinogenesis through a wide literature search of novel compounds that alone or in combination with traditional drugs have been investigated or are currently under investigation in randomized clinical trials.

Expert opinion: The molecular therapies mainly discussed in this review are potential therapeutic candidates for more effective and specific treatments. In the genomic era, a deeper knowledge about molecular characteristics of cancer provides the hope for the development of better therapeutic approaches. Targeting both genetic and epigenetic alterations, attacking tumor cells using cell-surface markers overexpressed in tumor tissue, reactivating antitumor immune responses and identifying predictive biomarkers represent the emerging strategies and the major challenges.     

Mitoxantrone,cisplatin, and methyl-glyoxal bis-guanylhydrazone chemotherapy for refractory malignant lymphoma: A Southwest Oncology Group phase II trial

Summary A phase II trial of combination chemotherapy with mitoxantrone, cisplatin, and methyl-glyoxal bix-guanylhydrazone (MGBG) was conducted in 32 patients with unfavorable histology malignant lymphoma. All patients had relapsed after only one prior chemotherapy regimen (CHOP — 56%; mBACOD — 28%). There were three complete and eight partial responses (overall response rate — 34%) among 32 eligible patients. The median duration of remission was 6.0 months. Severe granulocytopenia was common, with 19/32 patients (63%) suffering life-threatening, and 1/32 (3%) suffering fatal, granulocytopenia.We conclude that mitoxantrone-cisplatin-MGBG has modest activity as salvage treatment in malignant lymphoma patients, but produces severe toxicity. Address for offprints: Southwest Oncology Group (SWOG-8369), Operations Office, 5430 Fredericksburg Road, Suite #618, San Antonio, TX 78229, USA.     

三维斑点追踪技术评价蒽环类药物对淋巴瘤患者左室心肌功能损害的价值

目的 探讨三维斑点追踪成像（3D-STI）技术评价蒽环类药物对弥漫大B细胞淋巴瘤（DLBCL）患者早期左心室功能损害的价值。方法 选取2014年12月至2016年10月安徽医科大学第一附属医院行蒽环类药物化疗的DLBCL患者28例，分别于化疗前及化疗2、4、6个周期（即累计剂量达100、200、300 mg/m²）后24~48 h内行二维超声心动图及3D-STI检查，获取常规二维超声心动图数值及左心室整体面积应变（GAS）、整体纵向应变（GLS）、整体圆周应变（GCS）、整体径向应变（GRS），并进行统计学分析。结果 GAS、GLS在化疗4个周期[（-28.66±2.67）%，（-16.49±1.94）%]及6个周期[（-25.14±2.73）%，（-15.12±1.97）%]时，与化疗前[（-34.86±2.90）%，（-18.36±2.32）%]及化疗2个周期[（-34.05±2.09）%，（-17.75±1.91）%]时比较显著降低，差异有统计学意义（P<0.05）。Pearson相关分析显示，GAS与多柔比星累计剂量呈负相关（r=-0.815，P<0.05）。整个化疗进程中，GCS、GRS无明显变化。结论 GAS对DLBCL患者蒽环类药物化疗后出现早期左心室功损害的敏感性较高。3D-STI技术可以发现早期蒽环类药物所致的心脏毒性。     

Update on the pharmacotherapy for myelodysplastic syndromes

Introduction: For many decades, myelodysplastic syndromes (MDS) were a poorly understood disease group with no approved therapies, and patient management largely relied upon supportive care and intensive chemotherapy. The last decade has seen many scientific and therapeutic advances culminating in the US FDA approval of three drugs for the treatment of these complex malignancies: lenalidomide, azacitidine and decitabine.

Areas covered: This review summarizes the major prognostic risk models that guide treatment decisions and examines the available literature on the mechanism of action and efficacy of each of the approved agents. The authors also discuss evidence supporting the use of other therapies that have entered the standard of care including growth factors, immunosuppressive therapy and stem-cell transplantation.

Expert opinion: While significant progress has been made in understanding the molecular basis of MDS, much of this has yet to translate into therapeutic benefit. Each of the available treatment modalities has shortcomings, and both combination strategies and novel agents are under investigation in clinical trials to improve outcomes.     

Anti-angiogenic drugs currently in Phase II clinical trials for gynecological cancer treatment

Introduction: Numerous female patients suffer from gynecological cancers every year. When it comes to recurrent or chemoresistant cancers, there are limited treatment options. For decades, much enthusiasm has been shown for novel therapeutic strategies for cancers, and anti-angiogenesis agents appear to be a potential option. Since several promising angiogenesis inhibitors for certain cancers have been approved by Food and Drug Administration, more and more anti-angiogenic drugs are put into clinical trials.

Areas covered: In this review, the anti-angiogenic agents in Phase II clinical trials for gynecological cancer treatment are highlighted. This review mainly focuses on 5-year reports on angiogenesis inhibitors concerning ovarian cancer, cervical cancer, uterine leiomysarcoma and endometrial cancer. Inhibitors reviewed in this paper include bevacizumab, volociximab, aflibercept, temsirolimus, enzastaurin, trebananib, sunitinib, imatinib, pazopanib, sorafenib and nintedanib.

Expert opinion: These anti-angiogenic drugs while used either alone or in combination with chemotherapy, presented mixed results in treating gynecological cancers. The real challenge is how to take best advantage of the anti-angiogenesis hypothesis for therapeutic benefit. Much remains to be done before these molecules work efficaciously in treating gynecological cancer.