Prevention and treatment of veno-occlusive disease

OBJECTIVE: To review the current options for prevention and treatment of veno-occlusive disease in bone marrow transplant patients. DATA SOURCES: Articles were selected from a MEDLINE search (1966-October 1999) using the key terms veno-occlusive disease and bone marrow transplantation. In addition, references of all articles were examined for articles not found in the computer-based search. DATA EXTRACTION: All clinical trials, case-control studies, and case reports were evaluated. RESULTS: Heparin, low-molecular-weight heparin, prostaglandin E1, ursodiol, and glutamine have been studied for prevention of veno-occlusive disease. Heparin has been studied most extensively; however, no preventive regimen has a defined role in therapy. For treatment, tissue plasminogen activator has been evaluated most thoroughly, yet its safety and efficacy have not been clearly established in patients with veno-occlusive disease. Other possible treatment options include antithrombin-III, defibrotide, glutamine plus vitamin E, and surgery. CONCLUSIONS: Based on the available data, the most promising agents are ursodiol for prevention and defibrotide or glutamineplus vitamin E for treatment of veno-occlusive disease. Further clinical trials are needed to establish the appropriate preventive and treatment options available for bone marrow transplant patients suffering from veno-occlusive disease. To date, such decisions depend largely on poorly designed trials, case reports, and clinical experience.     

Anti-thrombin III in the management of hematopoietic stem-cell transplantation-associated toxicity

OBJECTIVE: To describe the evidence assessing the use of anti-thrombin III (AT-III) in the management of toxicity associated with hematopoietic stem-cell transplantation (HSCT)-conditioning regimens. DATA SOURCES: Clinical literature was accessed through conference proceedings, EMBASE, the Cochrane database, and MEDLINE (1966-December 2003). STUDY SELECTION AND DATA EXTRACTION: Case reports, small case series, case-control and cohort studies, and randomized controlled trials of AT-III in HSCT were evaluated. Publications examining AT-III use in the non-HSCT setting were also explored. Key search terms included AT-III, transplantation, and veno-occlusive disease (VOD). DATA SYNTHESIS: Severe VOD and ensuing multiple organ dysfunction is associated with high mortality in HSCT. A low AT-III level has been shown to correlate with the development of organ dysfunction. Phase II trials, case series, and one small, randomized, placebo-controlled study suggest a benefit when AT-III therapy is instituted early in the course of VOD/multiple organ dysfunction syndrome. In all of these reports, AT-III use was devoid of adverse events. CONCLUSIONS: Although further studies are needed to ascertain the optimal target level, method, and duration of administration, AT-III is still a viable alternative for the treatment of severe VOD and ensuing multiple organ dysfunction.     

Role of lenalidomide in the treatment of multiple myeloma and myelodysplastic syndrome

OBJECTIVE: To evaluate lenalidomide in the treatment of multiple myeloma and myelodysplastic syndrome (MDS). DATA SOURCES: Clinical literature was accessed through MEDLINE (1966-August 2005), Science Citation Index (1980-August 2005), and Proceedings of the American Society of Hematology (2000-2004). DATA SYNTHESIS: New analogs of thalidomide have been synthesized that are more potent and less toxic. Lenalidomide (CC-5013) is currently in Phase III trials for the treatment of multiple myeloma and MDS. Phase II trials demonstrated lenalidomide's efficacy in patients refractory to thalidomide. The full potential of this agent has yet to be proven, but preliminary data seem promising. CONCLUSIONS: Lenalidomide is a potent immunomodulating drug that offers different mechanisms of action and therapeutic potential for the treatment of multiple myeloma, MDS, and other malignancies.     

Effectiveness of defibrotide in the prevention of hepatic venooclusive disease among adult patients receiving allogeneic hematopoietic cell transplantation: A retrospective single center experience

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is one of the most life-threatening early complications following hematopoietic cell transplantation (HCT). Due to the high mortality rate of severe VOD/SOS accompanied with multiorgan failure, there is a great interest in preventive strategies. The efficacy of defibrotide (DF) on the prevention of VOD/SOS has been clearly shown in high-risk pediatric patients, but evidence-based data on adults is scarce. In this report, we aimed to assess the impact of DF on the incidence of VOD/SOS in our center by posttransplant day 30 among patients who were treated with allogeneic HCT (allo?HCT). The study included a total of 56 patiens (28 males, 28 females). The median age of the study cohort was 43 (20?68). The daily dose of DF was 10 mg/kg and 25 mg/kg in 53 (94.6 %) and 3 (5.3 %) patients, respectively. Patients also recieved oral ursodeoxycolic acid (UDCA) 250 mg three-times daily started with conditioning until D + 90. Twenty-three (41.1 %) patients had at least one major EBMT-defined risk factor for development of VOD/SOS. One patient who belonged to a very high-risk group (with at least two major risk factors) developed very-severe VOD/SOS at posttransplant D + 20 and died as a result of multiorgan failure. The cumulative incidence of VOD/SOS at D + 30 was 1.9 %. Our findings indicate that 10 mg/kg daily intravenous DF combined with UDCA is quite effective in prevention of VOD/SOS in patients who underwent first allo-HSCT.     

Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation in adult patients: Diagnosis,incidence, prophylaxis,and treatment

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) affecting the liver is a rare, possibly life-threatening complication of hematopoietic stem cell transplantation (HSCT). Sinusoidal endothelial cell (SEC) damage triggered by various factors (especially conditioning regimen) results in post sinusoidal portal hypertension due to obstruction of the hepatic vein. Diagnosis is guided by traditional clinical diagnostic criteria; the modified Seattle criteria, the Baltimore and revised European Group for Blood and Marrow Transplantation (EBMT), specifically. While there are promising results of imaging techniques studies in the diagnosis of VOD/SOS, none of those imaging techniques are routinely utilized in diagnosis yet. However, risk stratification is essential; conflicting results have been shown in studies aiming to define risk factors for development of VOD/SOS conducted to date. The only approved drug for the treatment of VOD/SOS yet is defibrotide, with early treatment offering higher chances of survival. In this review, we will focus on pathogenesis, clinical presentation and diagnostic criteria, risk factors, prophylaxis, and treatment of the VOD/SOS occurring post-HSCT.     

Bisphosphonates for malignancy-related bone disease: current status, future developments

This review relates to the efficacy and safety of bisphosphonates in metastatic bone disease. It discusses practical recommendations and possible future indications for bisphosphonate therapy. The current aims of bisphosphonates for metastatic bone disease are to prevent skeletal-related events (SREs), reduce bone pain and improve quality of life. Phase III clinical trials of clodronate and pamidronate have established their efficacy against bone complications in patients with breast cancer and multiple myeloma, while randomized trials have shown SRE reductions with zoledronic acid in patients with breast cancer and multiple myeloma, prostate cancer, and lung and other solid tumors. These bisphosphonates also have some effect on metastatic bone pain. Ibandronate is a new aminobisphosphonate, available in more than 40 countries outside of the US as intravenous and oral formulations for the prevention of skeletal events in patients with breast cancer and bone metastases. Phase III studies have shown that both intravenously and orally administered ibandronate have efficacy for the prevention of skeletal events and for the reduction of metastatic bone pain. In addition to efficacy, the long-term tolerability of bisphosphonates in metastatic bone disease influences drug selection. Besides their use in patients with established bone metastases, recent and ongoing research suggests that bisphosphonates also have clinical benefit in the adjuvant setting, and for the treatment of cancer-treatment-induced bone loss. Such interesting new developments may underpin a new era of bisphosphonate use sometime in the near future.Professor Body has received honoraria and grant support from Hoffmann-La Roche, and grant support from Novartis.     

NXY-059: review of neuroprotective potential for acute stroke

OBJECTIVE: To review available literature on the pharmacology, pharmacokinetics, efficacy, and tolerability of NXY-059, an investigational agent with a potential role in the treatment of acute stroke. DATA SOURCES: Information was obtained from a MEDLINE search (1966-February 2006) of English-language literature utilizing the following search terms: NXY-059, cerovive, nitrones, neuroprotection, free radical trapper, and secondary neurologic injury. STUDY SELECTION AND DATA EXTRACTION: Data from animal and human trials were evaluated to summarize the mechanism of action, efficacy, and safety of NXY-059. All published and unpublished trials and abstracts citing NXY-059 were selected. DATA SYNTHESIS: NXY-059 is an intravenous, nitrone-based, free radical trapping agent in Phase III trials for treatment of acute stroke. In various animal models, NXY-059 has shown reductions in infarct volume and neurologic deficits. Pharmacokinetic studies indicate that NXY-059 displays a predictable pharmacokinetic profile and primarily undergoes renal elimination. Results from 2 Phase II clinical trials showed favorable results for the safety and tolerability of the drug. A recent analysis of one of the Phase III trials showed a statistically significant reduction in the primary outcome of disability after acute stroke in patients who received NXY-059 compared with placebo. CONCLUSIONS: NXY-059 is a novel agent undergoing worldwide Phase III trials. Initial safety and efficacy data have not revealed any serious adverse events requiring special monitoring and/or precautions, with the exception of drug accumulation in patients with renal insufficiency. The potential benefit of this agent can change the current management algorithm for acute stroke and may represent significant advancement for the care of these patients.     

Expanding role of bortezomib in multiple myeloma: nursing implications

Multiple myeloma is the second most common hematologic malignancy and remains incurable, despite advances in chemotherapy and stem cell transplantation. Bortezomib, a novel proteasome inhibitor, is approved for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. In the assessment of proteasome inhibition for extending remissions phase III trial of bortezomib versus high-dose dexamethasone, bortezomib led to significantly longer survival and time to progression and higher response rate in patients with relapsed multiple myeloma. The principal adverse events were gastrointestinal effects, fatigue, transient thrombocytopenia, and reversible peripheral neuropathy. The side effect profile of bortezomib is extensively characterized, predictable, and generally manageable; retreatment or extended bortezomib therapy seems well tolerated. Nurses play a unique role in bortezomib treatment: they are often closest to the patients and are most able to educate patients about side effects and, if necessary, take appropriate action, independently or collaboratively with healthcare team members. In this review, we present the latest efficacy and safety data for bortezomib in relapsed multiple myeloma and characterize common side effects associated with bortezomib and the implications for nursing. We also highlight practical strategies for preventing and managing side effects, thereby enhancing the clinical benefit of bortezomib-based therapies to patients.     

Zalutumumab in head and neck cancer

INTRODUCTION: Over 90% of head and neck cancers overexpress EGFR. This correlates with advanced disease stage and worse prognosis. Strategies to inhibit the EGFR pathway have been developed over the last decade. Zalutumumab is a recent high-affinity completely human IgG1k antibody targeting EGFR. AREAS COVERED: The mechanism of action and data on efficacy and safety of zalutumumab in head and neck cancer. EXPERT OPINION: Zalutumumab has demonstrated acceptable toxicity in head and neck cancer patients, with rash being the most common adverse event. The toxicity profile makes zalutumumab an attractive option for patients who are heavily pretreated and/or have poor performance status due to concurrent co-morbidities. As the molecule is fully human, the likelihood of hypersensitivity to the drug is low. Zalutumumab may be effective at low concentrations through antibody-dependent cellular cytotoxicity. Current data from Phase I and II trials identify zalutumumab as a promising drug for the treatment of locally advanced head and neck cancer and recent data from a Phase III randomized trial showed encouraging survival results compared with best supportive care. Results from other ongoing Phase III trials will provide clarification on zalutumumab as a treatment option. The clinical development of this compound has been suspended from June 2011 until a development and commercialization partner is found.     

Ranpirnase--an antitumour ribonuclease: its potential role in malignant mesothelioma

Ranpirnase (Onconase) is a novel cytotoxic ribonuclease. In clinical development as a single agent in patients with malignant mesothelioma (MM), at 480 microg/m2 intravenously weekly, analysis of survival indicated prolonged periods of stable disease in Phase II trials and a potential survival benefit, compared with doxorubicin, in a small unpublished Phase III trial. In all clinical studies it has generally demonstrated a favourable safety profile except for easily controlled allergic reactions and dose modifications for renal impairment. Standard first-line treatment for MM has recently been established with an antifolate and cisplatin. At present, a Phase III trial of doxorubicin with or without ranpirnase is nearing completion in MM patients without prior chemotherapy or one prior chemotherapy regimen.     

Gene therapy for rheumatoid arthritis

Rheumatoid arthritis (RA) is a disabling, painful disorder affecting 1% of the world’s population. Although the aetiology of RA remains unknown, recent advances in understanding its pathophysiology have led to the characterisation of several proteins whose activities may be anti-arthritic. Clinical application of such proteins has greatly improved the treatment of RA, but the disease remains incurable and difficult to manage in a substantial number of patients. Thus, there are continued efforts to develop new therapeutic strategies. Because RA is a chronic condition, effective treatment will probably require the presence of therapeutic agents for extended periods of time. In the case of proteins, this is problematic. Gene therapy may offer a solution to this problem. Experimental studies have confirmed the feasibility, efficacy and safety of gene therapy for the treatment of animal models of arthritis. Several different approaches have shown promise in this regard, including gene transfer to the synovial lining cells of individual joints and the systemic delivery of genes to extra-articular locations. One unexpected finding has been the ‘contralateral effect’ in which gene delivery to one joint of an animal with polyarticular disease leads to improvement of multiple joints. Investigation of this phenomenon has led to interest in cell trafficking and the genetic modification of antigen-presenting cells (APC). The first Phase I clinical trial tested the feasibility and safety of ex vivo gene transfer to the synovial lining of human joints. This clinical trial has been successfully completed and two other Phase I trials are in progress. A Phase II study is now being planned to investigate the efficacy of gene transfer to the joints of patients with early stage RA.     

Kinoid of human tumor necrosis factor-alpha for rheumatoid arthritis

INTRODUCTION: Anti-TNF-α drugs have dramatically changed treatment of rheumatoid arthritis (RA) in terms of both clinical control and articular damage prevention. Despite this, they hold some important drawbacks, such as frequent therapeutic failures and high costs. Anti-TNF-α active immunization, with a therapeutic vaccine against TNF-α, is a promising alternative anti-TNF-α targeting strategy, potentially devoid of treatment limitations of some of current anti-TNF blocking agents. AREAS COVERED: This review covers the preclinical proof-of-concept of anti-TNF-α vaccination with the kinoid of human TNF-α (TNFK) and analyzes the body of evidence forming the rationale for the application of this strategy in RA and other TNF-α-dependent diseases. We describe the theoretical bases of anti-TNF-α active immunization and of experimental data supporting the applicability of TNFK to human disease in terms of both safety and efficacy. EXPERT OPINION: Based on preclinical efficacy and safety data supporting its feasibility in a Phase I - II trial in Crohn's disease, anti-TNF-α vaccination with TNFK has entered the phase of clinical development and promises to be a valuable anti-TNF-α targeting strategy in human disease. The focus is made in the first clinical trial in RA (Phase II) on the efficacy in active RA patients having developed antibodies against anti-TNF mAbs.     

Solanezumab for Alzheimer's disease

INTRODUCTION: Alzheimer's disease (AD) is a debilitating neurodegenerative illness affecting over 35 million people worldwide. Solanezumab is a monoclonal antibody that binds to β-amyloid (Aβ), a protein that plays a key role in the pathogenesis of AD. The drug is currently being investigated in Phase III trials as a disease-modifying treatment for AD. AREAS COVERED: This paper reviews literature on solanezumab that is available in PubMed from 2008 to 2010, other treatment trials in clinicaltrials.gov and published abstracts from conferences. The article also provides a discussion of the early trials of AN1792 and an overview of the immunotherapies currently in development. The authors provide the reader with a critical appraisal of the to-date clinical trial data on solanezumab and its implications for the broader field of immunotherapies for AD. EXPERT OPINION: Solanezumab can neutralize soluble Aβ peptides, which may represent the more neurotoxic of the Aβ species. Phase II findings support the compound's safety, which has been a concern for some Aβ immunotherapies. Cerebrospinal and plasma biomarker changes with solanezumab treatment are encouraging. Results of the ongoing Phase III trials will be instrumental in determining the drug's clinical significance.     

Economic Burden of Veno-occlusive Disease in Patients With B-cell Acute Lymphoblastic Leukemia in the United States

Purpose

The goal of this study was to evaluate the incidence, inpatient mortality, and economic burden of hepatic veno-occlusive disease (VOD) in adults with B-cell acute lymphoblastic leukemia (ALL) in the United States.

The use of ustekinumab in autoimmune disease

Importance of the field: The advent of biologic therapies has revolutionized the treatment of autoimmune diseases including psoriasis, autoimmune arthritides and inflammatory bowel disease. With recent advances in our understanding of the immunogenetic pathways involved in the pathogenesis of these conditions, newer, more targeted biologic therapies have been developed. Ustekinumab is an antibody to the common p40 subunit of IL-12 and IL-23, which has been studied in the treatment of psoriasis, psoriatic arthritis, Crohn's disease and multiple sclerosis.

Areas covered in this review: This review details the efficacy and safety of ustekinumab in all clinical studies to date, using PubMed listed publications and official product websites.

What the reader will gain: Readers will gain a comprehensive understanding of the mechanism of action of ustekinuamb, its pharmacodynamic and pharmacokinetic profile, and its clinical efficacy and safety in the treatment of psoriasis, psoriatic arthritis, Crohn's disease and multiple sclerosis.

Take home message: Ustekinumab has shown significant efficacy in the treatment of chronic plaque psoriasis in Phase III studies, and promising results in Phase II studies in psoriatic arthritis. Efficacy has been shown in Crohn's disease only in non-responders to infliximab. Ustekinumab did not show benefit in the treatment of multiple sclerosis.     

Insights into defibrotide: an updated review

Defibrotide is a polydisperse oligonucleotide with antiatherosclerotic, anti-inflammatory, anti-ischaemic, pro-fibrinolytic and antithrombotic actions without significant systemic anticoagulant effects. It has been used in the treatment of various cardiovascular disorders, and especially in endothelial complications of allogeneic stem-cell transplantation. We reviewed the published work for the mechanism of action and clinical use of defibrotide to consolidate data and to describe new applications of this drug. We reviewed the most relevant papers on defibrotide published from November 1982 to January 2008. (selected through PubMed), and used recent meeting abstracts as sources for this review. Reports have suggested that defibrotide has clinical efficacy for treatment and prophylaxis of hepatic sinusoidal obstruction syndrome occurring after stem-cell transplantation. Animal models have clearly shown the potential antineoplastic effect of this drug. Further clinical investigations are needed to clarify this new application.     

Abagovomab for ovarian cancer

INTRODUCTION: Ovarian cancer (OC) is the fifth most common cancer in women. Unfortunately, more than 70% of cases are detected at an advanced stage with a risk of recurrence, after front line therapy, of over 75%. The need for new therapeutic strategies is extremely high. AREAS COVERED: The development status and the possible role of specific immunotherapy of abagovomab are discussed in the context of the possible therapeutic options for maintenance therapy in advanced OC. An overview of abagovomab, generation and mechanism of action, Phase I/II results and the status of the Phase II/III ongoing trial is given. EXPERT OPINION: Abagovomab stimulates the humoral immune response and the cell-mediated immune response in the studies conducted to date. In the proof of concept (POC) study abagovomab prolonged overall survival in those OC recurrent patients who showed an immune response. Abagovomab has an excellent safety and tolerability profile. These characteristics make abagovomab an optimal candidate for a maintenance treatment for OC patients after frontline therapy. The final results of the Phase II/III pivotal study evaluating abagovomab in this setting will be available in the first half of 2011.     

Optimizing the efficacy and safety of bortezomib in relapsed multiple myeloma

Bortezomib (Velcade, Millennium) is the first proteasome inhibitor to be used in clinical practice and is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Bortezomib inhibits the intracellular degradation of proteins necessary for normal cell cycling and function. This, in turn, results in cell-cycle arrest and apoptosis. Bortezomib has shown significant activity in trials of patients with relapsed or refractory multiple myeloma; approximately one third of patients have shown significant improvement with bortezomib monotherapy in phase II and III clinical trials. Early phase trials are also evaluating bortezomib in combination with other agents used in the treatment of multiple myeloma, including melphalan, prednisone, thalidomide, and lenalidomide. Preliminary data suggest that bortezomib may act synergistically with some agents, and improves response rates. Bortezomib is generally well tolerated, but common side effects include peripheral neuropathy and thrombocytopenia. Studies are underway to explore different dosing strategies as well as ways to maximize patient benefit while reducing toxicity. This review will discuss what is known thus far about the efficacy and safety profile of bortezomib, ways for optimizing treatment with bortezomib, and strategies for managing side effects and enhancing quality of life.     

Carfilzomib in multiple myeloma

Introduction: Advances in drug therapy for multiple myeloma (MM) during the previous decade have improved survival outcomes; however, the disease remains incurable as patients eventually relapse or become refractory to all available therapies. Therefore, there is a clear need for more effective and well-tolerated treatments.

Areas covered: We review preclinical and clinical data regarding the use of carfilzomib, a proteasome inhibitor that is structurally and mechanistically distinct from bortezomib, for the treatment of MM patients. Carfilzomib pharmacokinetics, pharmacodynamics, efficacy, safety and tolerability are summarized, based on Phase I/II trial data.

Expert opinion: Carfilzomib represents a significant advance in the management of relapsed and/or refractory MM patients, including those intolerant or resistant to bortezomib. High response rates have been demonstrated with carfilzomib as a single agent or in combination with alkylating agents, immunomodulators and corticosteroids, even among patients who have failed multiple prior therapies. Carfilzomib also has significant potential in the frontline setting, with encouraging response and survival rates observed for combination regimens. Further evaluation of carfilzomib-containing regimens is ongoing in Phase III trials and investigator-sponsored studies, which include combinations with novel investigational agents. These findings will shape the future role of carfilzomib for MM patients across multiple settings.     

Rozrolimupab, symphobodies against rhesus D, for the potential prevention of hemolytic disease of the newborn and the treatment of idiopathic thrombocytopenic purpura

Currently under codevelopment by Symphogen and Swedish Orphan Biovitrum, rozrolimupab is the first in a new class of recombinant polyclonal antibodies, known as symphobodies, produced using a proprietary technology from Symphogen. Rozrolimupab is being investigated for the prevention of hemolytic disease of the fetus and newborn (HDFN) and for the treatment of idiopathic thrombocytopenic purpura (ITP). Rozrolimupab comprises 25 genetically unique IgG1 antibodies, all of which are specific for the rhesus D (RhD) erythrocyte protein. In preclinical studies, rozrolimupab demonstrated binding to erythrocytes that was comparable with that of two plasma-derived anti-D Ig preparations. In a phase I clinical trial in healthy male volunteers, treatment with rozrolimupab was not associated with serious adverse events. In a phase II clinical trial of rozrolimupab in healthy, male, RhD-negative volunteers, rozrolimupab dose-dependently cleared RhD-positive erythrocytes from the circulation. Phase II clinical trials in ITP and HDFN are currently ongoing. Phase III clinical trials are necessary to establish the efficacy and safety profile of rozrolimupab compared with standard plasma-derived anti-D Ig preparations.