Gallium nitrate for the treatment of non-Hodgkin's lymphoma

Mortality from non-Hodgkin's lymphoma (NHL) is high, thus defining the need for additional therapeutic agents for this disease. Gallium nitrate is a metal compound that is presently approved for the treatment of hypercalcaemia associated with malignancy. In clinical trials first conducted over two decades ago, this drug was found to have antineoplastic activity in NHL. However, its development as an antineoplastic agent for the treatment of NHL was never rigorously pursued. Gallium has unique mechanisms of action that include its binding to transferrin in the circulation and targeting transferrin receptors present on lymphoma cells. As it shares chemical properties with iron, gallium can disrupt critical steps in iron homeostasis that are essential for tumour cell viability and growth and can inhibit the iron-dependent activity of ribonucleotide reductase. The drug may also target other cellular processes unrelated to iron. Phase I/II studies have shown that gallium nitrate displays the most efficacy and lowest toxicity in NHL when administered as a continuous intravenous infusion, producing response rates of 43% in patients with relapsed or refractory NHL. It does not suppress the white blood cells or platelets and does not share cross-resistance with other chemotherapeutic drugs. These characteristics make it particularly attractive for the treatment of myelosuppressed patients and for incorporation into combination therapy. Multi-institutional Phase II clinical trials are in progress to evaluate gallium nitrate as a single agent or in combination. These studies will help define its role in the current treatment of NHL.     

Monoclonal antibodies in the treatment of lymphoid leukemia

MoAb-based therapies are evolving into the first broad-spectrum class of targeted anti-leukemic therapy. Developments in many areas, including computer modeling of receptors and ligands, and increasing sophistication in recombinant technologies may result in a rapid increase in the number and complexity of MoAb available. We can anticipate an increase in the number of safer conjugates being delivered to leukemia cells. Further understanding of the in-vitro mechanisms involved in tumor cell killing by MoAb will be important in maximizing the efficacy of this approach.     

Monoclonal antibodies in the treatment of neuroimmunological diseases

Over the past 25 years, monoclonal antibodies (mAb) have become important elements in the therapeutic concepts for numerous clinical specialities, including oncology, gastroenterology, hemostaseology and endocrinology. One of the most dynamic fields of their use is the treatment of autoimmune diseases. Although the number of existing mAb interfering with the immune system has increased remarkably and many studies have yielded encouraging results in the treatment of neuroimmunological diseases, their clinical use is still limited compared with standard treatments. The only mAb which has been approved for a neuroimmunological disease by now is natalizumab for the treatment of relapsing-remitting multiple sclerosis (RRMS). This article gives an overview on mAb that are currently in use or under investigation for treating neuroimmunological diseases like multiple sclerosis (MS), neuromyelitis optica (NMO), chronic inflammatory demyelinating polyneuropathy (CIDP), inclusion body myositis (IBM), dermatomyositis, polymyositis, opsoclonusmyoclonus syndrome (OMS), multifocal motor neuropathy (MMN), anti-myelin-glycoprotein neuropathy (Anti-MAG), stiff person syndrome and myasthenia gravis (MG).     

Antibody-targeted immunotherapy for treatment of non-Hodgkin's lymphoma

The scientific development of immunotherapies and radioimmunotherapies of cancer began more than four decades ago. Over time, it has become apparent that the choice of target antigen, immunogenicity of antibodies, length of antibody half-life, ability of antibodies to recruit immune effector functions, decision on conjugation of antibodies to toxins or radionuclides and antibody manufacturing are critical components of successful development of an immunotherapeutic regimen. Anti-idiotype antibodies were some of the first successful monoclonal antibody treatments developed for non-Hodgkin's lymphoma. In 1997, the chimeric antibody, Rituximab, was approved by the United States Food and Drug Administration for treatment of patients with relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. In an effort to enhance the efficacy of immunotherapy, toxins and radionuclides have been conjugated to monoclonal antibodies. Ibritumomab, the parent murine antibody of Rituximab, is conjugated to the radioisotope 90Y to create 90Y Ibritumomab tiuxetan, (90Y Zevalin, IDEC-Y2B8). Promising Phase I/II trials have been completed. Phase III experimental trials of 9Y Ibritumomab tiuxetan as treatment for relapsed or refractory NHL are in progress.     

The role of pixantrone in the treatment of non-Hodgkin's lymphoma

Pixantrone is an anthraquinone-based inhibitor of topoisomerase II. It is similar to both the anthracycline doxorubicin and the anthracenedione mitoxantrone, but lacks the 5,8-dihydroxy substitution pattern of mitoxantrone, and has a tricyclic system unlike the tetracyclic structure seen with anthracyclines. Anthracyclines are the most active drugs in lymphoma therapy, but their use is limited by their cumulative and irreversible cardiotoxicity. Pixantrone was developed to improve the toxicity profile of the current anthracyclines and anthracenediones while maintaining their activity. Interestingly, pixantrone showed no measurable cardiotoxicity compared with its parent compound mitoxantrone or other anthracyclines at equi-effective doses in several animal models. Together with its superior cytotoxic activity in leukaemia and lymphoma models, these features render the drug a promising candidate for clinical development in indolent and aggressive non-Hodgkin's lymphoma. In this review, the latest results of the use of pixantrone in indolen-t and aggressive non-Hodgkin's lymphomas are summarised.     

Novel treatment strategies for aggressive non-Hodgkin's lymphoma

The World Health Organization has included different types of lymphoma under the aggressive category. In the US, diffuse large B-cell lymphoma is the most common aggressive lymphoma and accounts for > 30% of the 55,000 new cases diagnosed annually. Recent advances in the knowledge of the molecular biology have provided an increased understanding of the heterogeneity of non-Hodgkin's lymphoma. New treatments, especially those with the use of monoclonal antibodies, are improving both the survival and the response rate.     

Rituxan immunotherapy and zevalin radioimmunotherapy in the treatment of non-Hodgkin's lymphoma

Immunotherapy with the anti-CD20 monoclonal antibody rituximab has been shown in clinical trials to be effective in the treatment of both indolent and aggressive non-Hodgkin's lymphomas (NHL). Recent studies have demonstrated improved clinical benefit with extended dose and maintenance therapies in patients with indolent lymphomas and chronic lymphocytic leukemia. Rituximab's label was recently expanded to include treatment of bulky disease, retreatment of patients previously treated with rituximab, and an eight-week extended treatment schedule. Rituximab has also been effectively combined with chemotherapy, resulting in higher response rates and longer response durations in randomized trials in patients with aggressive lymphoma. Studies continue to evaluate and expand the role of rituximab in the treatment of NHL, including its use in combined immunotherapy approaches and autologous stem cell transplant as well as in the treatment of autoimmune disorders. Radioimmunotherapy with the rituximab and ibritumomab tiuxetan (Zevalin) regimen was recently approved for the treatment of relapsed or refractory low-grade, follicular or CD20+ transformed NHL, including rituximab refractory follicular NHL. The regimen is delivered on an outpatient basis over the course of a week. Studies are currently exploring sequential dose therapy, radioimmunotherapy with rituximab maintenance, and ibritumomab tiuxetan radioimmunotherapy as part of autologous stem cell transplant. Current understanding of the mechanisms of action of rituximab and the use of rituximab and ibritumomab tiuxetan in patients with indolent and aggressive NHL will be discussed.     

Current treatment of follicular and low-grade non-Hodgkin's lymphoma

Patients with low-grade non-Hodgkin's lymphoma (NHL) have a median survival of 4-8 years from diagnosis and a cause-specific survival of about 10 years. Radiotherapy can be curative in a small proportion of patients with very localized disease, but the majority of patients have advanced disease at diagnosis and it is not clear that any current therapy is curative in this situation. While in many instances patients with high-grade NHL are cured by chemotherapy, those with low-grade NHL, despite impressive response rates, almost invariably relapse. A 'watch-and-wait' strategy can therefore delay the onset of chemotherapy by 2-3 years, without affecting survival. Results with autologous stem cell transplantation have been similarly disappointing to date. Rituximab is a human-mouse chimeric monoclonal antibody that represents a novel approach to treatment of low-grade NHL, targeting malignant cells without the side effects associated with chemotherapy. A pivotal study has demonstrated a response rate of 56% in relapsed or refractory low-grade NHL. The relatively benign side-effect profile means rituximab can be used early in the disease process, and in combination with chemotherapeutic regimens and autologous transplantation. Ongoing and future studies will define the optimal role of rituximab in treatment of low-grade NHL.     

Pharmacokinetic evaluation of pixantrone for the treatment of non-Hodgkin's lymphoma

INTRODUCTION: Pixantrone is a novel aza-anthracenedione, similar in structure to anthracyclines, including the anthracycline derivative mitoxantrone. There is no standard therapy for relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL) in patients who have received two prior lines of therapy. Pixantrone does not bind iron, promotes reactive oxygen species to a lesser degree than other anthracyclines and is therefore believed to be less cardiotoxic without compromising efficacy. AREAS COVERED: This article outlines the chemical properties of pixantrone, as well as the preclinical and clinical studies looking at pixantrone in the treatment of both indolent and aggressive NHL. EXPERT OPINION: Pixantrone is an active and safe drug that has been shown to be of benefit when used to treat patients with relapsed aggressive NHL in the context of Phase II and Phase III studies. It was superior to other single-agent therapies in this context and in combination therapy may be the treatment of choice in order to avoid cardiac toxicity. Potentially it is a more effective and less cardiotoxic alternative to doxorubicin in patients with aggressive NHL.     

Monoclonal antibodies for the treatment of Ebola virus disease

Introduction: To date, the management of patients with suspected or confirmed Ebolavirus disease (EVD) depends on quarantine, symptomatic management and supportive care, as there are no approved vaccines or treatments available for human use. However, accelerated by the recent large outbreak in West Africa, significant progress has been made towards vaccine development but also towards specific treatment with convalescent plasma and monoclonal antibodies.

Areas covered: We describe recent developments in monoclonal antibody treatment for EVD, encompassing mAb114 and the MB-003, ZMAb, ZMapp? and MIL-77E cocktails.

Expert opinion: Preventive measures, are, and will remain essential to curb EVD outbreaks; even more so with vaccine development progressing. However, research for treatment options must not be neglected. Small-scale animal and individual human case studies show that monoclonal antibodies (mAbs) can be effective for EVD treatment; thus justifying exploration in clinical trials. Potential limitations are that high doses may be needed to yield clinical efficacy; epitope mutations might reduce efficacy; and constant evolution of (outbreak-specific) mAb mixtures might be required. Interim advice based on the clinical experience to date is that treatment of patients with mAbs is sensible, provided those could be made available in the necessary amounts in time.     

治疗非霍奇金淋巴瘤新药:匹杉醇

匹杉醇为一新型蒽环类药物,已由欧盟批准单独用于治疗成人复发难治侵袭性B细胞非霍奇金淋巴瘤。Ⅲ期临床试验结果提示,作为复发难治侵袭性非霍奇金淋巴瘤的单一替换疗法,匹杉醇的疗效明显优于单独应用长春瑞滨、奥沙利铂、异环磷酰胺、依托泊苷、米托蒽醌、吉西他滨等对照药物。患者对匹杉醇易于耐受,与其他蒽环类药物相比,匹杉醇的心脏毒性较低,骨髓抑制为其最常引起的不良事件。     

Monoclonal antibodies for the treatment of acute myeloid leukemia

Currently, patients with acute myeloid leukemia (AML) are treated with cytotoxic chemotherapy and hematopoietic stem cell transplantation (HSCT). With this approach, the majority of patients still die of their disease because of both treatment-related mortality and relapse. Recently, monoclonal antibodies and immunoconjugates have been developed which potentially may increase the efficacy of treatment and decrease morbidity and mortality by specifically targeting the malignant cell. Unconjugated monoclonal antibodies have shown only moderate activity. A second, more effective, approach involves antibody conjugation with radioactive particles or chemotherapeutic agents, such as, immunotoxins, targeted delivery of cell killing. The antigens CD33, CD45, and CD66, are three antigens to which monoclonal antibodies have been directed. Most experience has been with gemtuzumab ozogamicin (Mylotarg) which is an immunoconjugate of an anti-CD33 antibody chemically linked to a potent cytotoxic agent, calicheamicin. Gemtuzumab ozogamicin appears to be particularly active in patients with acute promyelocytic leukemia, possibly related to the high expression of the CD33 antigen on the cell surface. Although gemtuzumab ozogamicin has activity as a single agent, the most promising result may be seen when this agent is combined with conventional cytotoxic chemotherapy. Preliminary studies have suggested a high complete remission rate and randomized clinical trials are underway. A unique potential toxicity has been identified, namely venoocclusive disease or sinusoidal obstructive syndrome which may be problematic among patients who subsequently undergo HSCT. An additional strategy includes radiolabeled monoclonal antibodies to intensify the conditioning regimen prior to HSCT. The most promising results have been obtained with radiolabeled anti-CD45 antibodies.     

Monoclonal antibodies in the treatment of cancer, Part 1.

Monoclonal antibodies used in the treatment of cancer are discussed. Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. In addition to having direct cellular effects, antibodies can carry substances, such as radioactive isotopes, toxins, and antineoplastic agents, to the targeted cells. Five monoclonal antibodies--rituximab, trastuzumab, gemtuzumab ozogamicin, alemtuzumab, and ibritumomab tiuxetan--are available for clinical use. Rituximab is active against indolent lymphomas, providing a valuable alternative for patients with relapsed or refractory disease. Rituximab plus cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) increased survival over CHOP alone in patients with high-grade lymphomas. Trastuzumab has significant activity against HER-2-positive breast cancer, especially in combination with paclitaxel or an anthracycline and cyclophosphamide. Gemtuzumab ozogamicin is an active second-line therapy in older patients with acute myelogenous leukemia, but its role in combination regimens is unclear. Alemtuzumab is a valuable option for salvage therapy of patients with chronic lymphocytic leukemia. Ibritumomab tiuxetan delivers radioactive isotopes to tumor cells and is active against indolent lymphomas in patients who have relapsed after chemotherapy or rituximab therapy. The most common adverse effects of monoclonal antibodies are myelosuppression, infusion-related reactions, and hypersensitivity reactions. Rituximab may cause tumor lysis syndrome, arrhythmias, and pulmonary dysfunction. Alemtuzumab causes immunosuppression, increasing the risk of infection. Gemtuzumab ozogamicin may cause hepatotoxicity, and trastuzumab may cause significant pulmonary or cardiac toxicity. Investigational monoclonal antibodies include edrecolomab and tositumomab. Monoclonal antibodies have a significant role in the management of patients with advanced refractory or relapsed lymphomas and leukemias.     

Monoclonal antibodies in the treatment of cancer, Part 2.

Monoclonal antibodies used in the treatment of cancer are discussed. Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. In addition to having direct cellular effects, antibodies can carry substances, such as radioactive isotopes, toxins, and antineoplastic agents, to the targeted cells. Five monoclonal antibodies--rituximab, trastuzumab, gemtuzumab ozogamicin, alemtuzumab, and ibritumomab tiuxetan--are available for clinical use. Rituximab is active against indolent lymphomas, providing a valuable alternative for patients with relapsed or refractory disease. Rituximab plus cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) increased survival over CHOP alone in patients with high-grade lymphomas. Trastuzumab has significant activity against HER-2-positive breast cancer, especially in combination with paclitaxel or an anthracycline and cyclophosphamide. Gemtuzumab ozogamicin is an active second-line therapy in older patients with acute myelogenous leukemia, but its role in combination regimens is unclear. Alemtuzumab is a valuable option for salvage therapy of patients with chronic lymphocytic leukemia. Ibritumomab tiuxetan delivers radioactive isotopes to tumor cells and is active against indolent lymphomas in patients who have relapsed after chemotherapy or rituximab therapy. The most common adverse effects of monoclonal antibodies are myelosuppression, infusion-related reactions, and hypersensitivity reactions. Rituximab may cause tumor lysis syndrome, arrhythmias, and pulmonary dysfunction. Alemtuzumab causes immunosuppression, increasing the risk of infection. Gemtuzumab ozogamicin may cause hepatotoxicity, and trastuzumab may cause significant pulmonary or cardiac toxicity. Investigational monoclonal antibodies include edrecolomab and tositumomab. Monoclonal antibodies have a significant role in the management of patients with advanced refractory or relapsed lymphomas and leukemias.     

美罗华联合CHOP治疗B细胞性非霍奇金淋巴瘤

目的评价美罗华(Rituximah)联合CHOP(R-CHOP)方案治疗CD20阳性B细胞性非霍奇金淋巴瘤(NHL)的临床疗效及不良反应。方法将60例初治B细胞淋巴瘤患者分为R-CHOP组和CHOP组各30例。R-CHOP组采用R-CHOP方案化疗;CHOP组采用CHOP方案化疗。6个疗程后比较两组的临床疗效及不良反应。结果 R-CHOP组完全缓解率达80%,总有效率90%;CHOP组完全缓解率为60%,总有效率为73.3%,两组疗效差异有统计学意义(P<0.01)。两组不良反应差异无统计学意义(P>0.05)。结论美罗华联合CHOP方案治疗CD20阳性B细胞性非霍奇金淋巴瘤疗效显著,不良反应与单纯化疗相似,可作为该病目前的首选方案。     

Antiangiogenic therapies in non-Hodgkin's lymphoma

The tumor microenvironment is critical in the initiation and progression of cancerous growth, which is dependent on the establishment of a functional vascular network supporting neoplastic proliferation. While the precise role of tumor angiogenesis in lymphoma pathogenesis remains under active investigation, emerging data on the proangiogenic properties of the neoplastic lymphoma cells and mechanism of vascular assembly suggest that angiogenesis is highly relevant to the biology and therapy of non-Hodgkin's lymphoma. Antiangiogenic therapies in non-Hodgkin's lymphoma are in various stages of clinical development aiming at distinct angiogenic pathways operative in endothelial cells and perivascular stromal cells. The major classes of available antiangiogenics include anti-VEGF, small molecule inhibitors targeting proangiogenic receptor tyrosine kinases and their downstream signal transduction pathways, as well as immunomodulatory compounds with antiangiogenic properties. Preliminary clinical data indicate therapeutic advantages associated with strategies targeting dual compartments of vascular cells and tumor cells, as well as multiple angiogenic pathways within the tumor microenvironment. This review summarizes recent applications of antiangiogenic strategies in non-Hodgkin's lymphoma based on current understanding of the biology of lymphoma angiogenesis.     

Treatment advances in non-Hodgkin's lymphoma

Non-Hodgkin's lymphomas (NHL) encompass a heterogeneous group of lymphoid malignancies with varying natural histories and prognoses. Recent classifications for NHL have defined distinct lymphoma entities based on morphology, immunophenotype, genetic features, clonal cell lineage and clinical features. These new, more precise classifications and characterizations of NHL will be essential in developing new targeted therapies. However, for this brief review, we will continue describe NHL primarily as indolent or aggressive. Treatment options for patients with indolent, but generally incurable, lymphomas include a 'watch and wait' approach, single agent alkylators, nucleoside analogues, combination chemotherapy, immunotherapy with monoclonal antibodies, radiolabelled monoclonal antibodies, or interferon (IFN). Vaccine therapy for indolent lymphomas is currently under intense investigation. For aggressive lymphomas, combination chemotherapy remains the standard of care. Major advances in the management of aggressive lymphomas include validation of the international prognostic index and clarification of the role of high-dose therapy with bone marrow or stem cell transplant in patients with relapsed aggressive lymphomas. Multiple randomised pilot trials of high dose therapy as initial therapy for aggressive lymphomas have shown conflicting results and await confirmatory studies.