Pharmacotherapy of myelodysplastic syndromes

Importance of the field: Despite the remarkable progress in the treatment of patients with myelodysplastic syndromes (MDS) in the past decade, response to the hypomethylating agents azacitidine and decitabine in non-del(5q) MDS patients remains at ～ 50%, leaving half of patients needing treatment with essentially no options. As biologic insight into the molecular pathways that account for disease evolution and clinical heterogeneity is expanded, the arsenal of potential drugs that may elicit significant response is also increasing. One of the greatest challenges for the treating physician is to decide when to initiate therapy and which therapy (approved drug or newer agents still in clinical trial) is likely to be the most beneficial. While there is no single answer to these issues, there are several approaches that may be considered, and these are addressed in this review.

Areas covered in this review: This review examines the clinical outcomes of the FDA-approved drugs as well as of the promising new therapies that are in current clinical trials.

What the reader will gain: The clinician now has multiple treatment options for patients with MDS. It is important to consider multiple factors before initiating therapy with disease-modifying drugs. This review presents some of the decision-making approaches that are in practice at present.

Take home message: For the first time, various treatment options are available for patients with MDS. In light of the intense efforts now in progress, the next decade promises to be one of hope and excitement for both MDS patients and treating clinicians.     

Emerging immunosuppressive drugs in myelodysplastic syndromes

Introduction: Myelodysplastic syndromes (MDS) are characterized by dysplastic morphologic features and ineffective hematopoiesis. Pathophysiological characteristics change over time making therapeutic development a major challenge. In early MDS, cytopenias arise or are exacerbated by humoral and cellular immune-mediators that suppress hematopoietic progenitor survival and alter the bone marrow microenvironment.

Areas covered: In this review, current immunosuppressive regimens are described. To identify new therapies that may enhance immunosuppressive therapy (IST) response and identify pharmacodynamic biomarkers for patient selection, the inflammasome, cytokines, metabolic pathways and signaling events are described.

Expert opinion: Agents with the potential to induce early, durable hematologic remissions are needed and many new immunosuppressive agents are available for investigation. An immune-mediated mechanism is likely to contribute to MDS early after diagnosis. New approaches that interfere with inflammatory pathways in the bone marrow microenvironment may move closer toward sustained disease control in MDS.     

Emerging biological therapies for the treatment of myelodysplastic syndromes

Introduction: No drug has resulted in a survival advantage in patients with lower-risk myelodysplastic syndromes (MDS). While hypomethylating agents (HMA) have revolutionized treatment options for patients with higher-risk MDS, the prognosis remains dismal after HMA treatment failure. Novel effective therapies are urgently needed especially after HMA failure.

Areas covered: This review covers the current approach to disease prognostication and risk-adaptive therapy, as well as novel therapeutic approaches. We discuss the recent advancements in the understanding of MDS disease biology as a basis of targeted drug development. Several classes of novel agents are reviewed including drugs targeting dysregulated epigenetic control mechanisms, signaling pathways, abnormal splicing, as well as agents that target the immune system and the MDS bone marrow niche.

Expert opinion: Significant advancements in the understanding of the underlying biology of MDS are only starting to be translated into novel treatment options for MDS. Epigenetic therapy has shown significant clinical activity with HMA but the results of clinical trials combining HMAs with histone deacetylase inhibitors (HDACi) have been disappointing to date. Similarly, targeting several aberrant pathways in MDS has not resulted in significant improvements in therapy. Future therapies will focus both on synergic combination of existing drugs as well as novel agents targeting dysregulated immune responses and abnormal RNA splicing in MDS.     

Update on immunomodulatory drugs (IMiDs) in hematologic and solid malignancies

Introduction: Thalidomide and its analogs [small molecule immunomodulatory drugs (IMiDs®)] are among the most successful new therapeutic agents of recent years. Thalidomide is now an integral part of multiple myeloma (MM) therapy. Lenalidomide has been approved for the treatment of patients with relapsed MM and 5q-myelodysplastic syndromes (MDS). Currently, more than 400 clinical trials are evaluating the activity of lenalidomide, alone or in combination with other conventional or novel therapies, in newly diagnosed MM and 5q-MDS. Based on their broad range of actions within the tumor microenvironment, IMiDs are currently also evaluated in a wide variety of additional hematologic and solid malignancies.

Areas covered: This paper reviews the historic development of thalidomide and its derivatives and presents novel insights into their mode of action. Moreover, it discusses up-to-date clinical trials investigating IMiDs and potential future research and therapeutic perspectives in MM and other malignancies.

Expert opinion: Although IMiDs have emerged as powerful agents for the treatment of hematologic and solid tumors, more preclinical and clinical studies are urgently needed both to increase our knowledge of their mechanisms of action, and to optimize their clinical use, in order to further improve the patient's quality of life and survival.     

Drug design strategies for the treatment of prostate cancer

Introduction: While metastatic prostate cancer remains an incurable tumor, remarkable progress has been made with novel drug design strategies for this incurable disease. Several new agents, including hormonal analogues, cytotoxic chemotherapy drugs, radionuclides and innovative targeted therapies, have recently been approved by the FDA for use in advanced and/or metastatic castrate-resistant prostate cancer. Furthermore, a growing number of new diagnostic or predictive genetic tests have also been incorporated into the management of this disease. Immunotherapy-based approaches have shown promise and have led to drug approvals. Other experimental approaches such as vascular targeting are in early translational clinical trials.

Areas covered: Herein, the authors outline select state-of-the-art approaches in the field. They also discuss the current challenges and future opportunities in the medical care of prostate cancer patients.

Expert opinion: An inherent challenge in the treatment of prostate cancer is to determine which patients need immediate aggressive treatment versus active surveillance. For patients needing aggressive treatment, integrating the sequence of therapeutic interventions, to provide the most benefit, remains a challenge that clinicians face. Recently, several genetic tests have been approved, facilitating early treatment decisions. Innovative targeted therapies are moving towards clinical applications, providing treatment options for tumors previously considered refractory to androgen ablation treatment.     

Emerging drugs for renal cell carcinoma

Importance of the field: The treatment of metastatic renal cell carcinoma (RCC) has evolved significantly over the past 5 years and targeted therapy has become the standard of care. However, complete and lasting responses to these drugs are still uncommon. Currently, novel agents are being tested in clinical trials.

Areas covered in this review: We discuss approved targeted agents in RCC and emphasize on emerging therapies. We searched the US National Library of Medicine (PubMed) using the terms ‘renal cell carcinoma’, ‘targeted therapy’ and ‘novel agents’, from 1990 to the present. We also searched for abstracts from the meetings of the American Society of Clinical Oncology and Genitourinary Cancers Symposium from 2007 to the present.

What the reader will gain: This paper provides understanding of the approved treatments for advanced RCC as well as the novel agents and their targeted biological pathways.

Take home message: Despite dynamic and recent advances in the management of metastatic RCC much about the molecular biology of this tumor has yet to be delineated. Even more so, strategies of sequential treatment, combination of targeted drugs, mechanisms of resistance, optimal dosages and scheduling remain areas of potential development interest.     

Emerging drugs for diabetic macular edema

Introduction: Diabetic macular edema (DME) is the most common cause of visual impairment due to diabetic retinopathy. The treatment of DME has recently undergone a paradigm shift. Traditionally, photocoagulation was standard treatment, but pharmacologic therapies are becoming increasingly used for this purpose. All currently available drug therapies for DME are either anti-VEGF agents or corticosteroids.

Areas covered: The pathogenesis of DME involves angiogenesis, inflammation and oxidative stress. The scientific rationale to treat DME through the pharmacologic blockade of VEGF and other pro-angiogenic factors is discussed. The fluocinolone insert is approved for the treatment of DME in several European countries, but not in the US at this time. Some medications that are already approved for other retinal diseases, most prominently aflibercept and the dexamethasone delivery system, have recently obtained approval for DME in the US. Other compounds are being studied in earlier-phase clinical trials.

Expert opinion: Pharmacologic treatment of DME will likely become increasingly used, especially for patients with edema involving the fovea. At this time, the two main classes of medication for treatment of DME are anti-VEGF agents and corticosteroids. As we continue to collect clinical trials data, the precise role of individual agents, and the continuing role for photocoagulation, will become more clear.     

Pediatric pulmonary arterial hypertension: current and emerging therapeutic options

Introduction: Pulmonary arterial hypertension (PAH) is a rare disease in neonates, infants and children that is associated with significant morbidity and mortality. An adequate understanding of the controlling pathophysiologic mechanisms is lacking and although mortality has decreased as therapeutic options have increased over the past several decades, outcomes remain unacceptable.

Areas covered: This review summarizes the currently available therapies for neonates, infants and children with PAH and describes emerging therapies in the context of what is known about the underlying pathophysiology of the disease.

Expert opinion: All of the currently approved PAH therapies impact one of three endothelial-based pathways: nitric oxide–guanosine-3′-5′cyclic monophosphate, prostacyclin or endothelin-1. The beneficial effects of these agents may relate to their impact on pulmonary vascular tone, and/or their antiproliferative and antithrombotic properties. Fundamental advances in PAH therapy are likely to relate to: i) a better understanding of PAH subpopulations, allowing for therapies to be better tailored to individual patients and pathophysiologic processes; and ii) therapies that promote the regression of advanced structural remodeling.     

Current investigational drugs in psoriasis

Introduction : The advent of biologic therapies has revolutionized the treatment of psoriasis. Increased understanding of immunogenetic pathways has allowed for the development of more selective targeted biologic therapies. Multiple new treatments are currently in development for the treatment of psoriasis. Preliminary data for many of these agents, particularly with regard to agents targeting the IL-23/Th17 pathway, are promising. Proven long-term safety, however, is an absolute necessity with newly developed drugs, and should, therefore, still be considered second-line agents to current established treatments with long-term safety data.

Areas covered : This review details the mechanisms of action of drugs currently in development or in clinical trials for the treatment of psoriasis, using clinical trial registries and associated publications. Readers will gain a comprehensive overview about the mechanism of action of emerging treatments targeting various immune pathways deeply involved in psoriasis. Pathogenesis, clinical efficacy and safety data for these treatments are discussed where available.

Expert opinion : Psoriasis remains a heavily undertreated systemic immune-mediated disease despite increased understanding of immunopathogenesis of the disease and advent of a multitude of novel therapeutic agents with potentially improved bioavailability and safety profiles. Limitations, however, remain in the realm of topical agents for treatment of mild to moderate psoriasis, which has seen little progress over the years. A concerted effort will need to be made among researchers, clinicians and patient advocacy groups to ensure new therapeutic agents are developed and gain proper exposure.     

Emerging drugs for pulmonary hypertension

Importance of the field: Pulmonary arterial hypertension (PAH) is a clinical syndrome characterized by structural narrowing of the small pulmonary arteries that often culminates in fatal right heart failure.

Areas covered in this review: PubMed was searched for PAH and treatment. Data from scientific meetings and pharmaceutical websites are also included. There are currently eight FDA approved drugs for PAH that fall into one of three classes: prostacyclins, endothelin-receptor antagonists and PDE-5 inhibitors. All have important limitations and morbidity and mortality remain high. Several new agents with similar mechanisms of action are in clinical development. Multiple novel therapeutic targets are being explored. New applications for PAH therapies, such as pulmonary hypertension due to left heart and lung disease, are also being investigated.

What the reader will gain: An understanding of currently available drugs and those in clinical development for pulmonary hypertension.

Take home message: Drugs targeting the pulmonary vasculature have been an extremely active area of basic and clinical research for the past 20 years and will continue to be so for the foreseeable future. Considerable progress has been made, and yet there continues to be a great unmet medical need for developing more efficacious therapies.     

Current treatment options and strategies for myelodysplastic syndromes

Background: The myelodysplastic syndromes (MDS) are a group of heterogeneous disorders characterized by ineffective hematopoiesis. A number of scoring systems have been developed but they are of limited value in guiding individual patient treatment decisions. Objective: We have presented the benefits and limitations of various treatment approaches for MDS to help provide guidance in treatment decisions. Methods: An extensive literature search on PubMed from 2000 to 2008 was done using MESH keywords MDS, treatment, 5-azacytidine, decitabine, lenalidomide, antithymocyte globulin. Conclusion: In recent years there has been progress in supportive care and three agents have been approved for the treatment of MDS. With the exception of lenalidomide, which produced remarkable responses with 5q chromosomal deletion, these therapies benefit a minority of patients and the overall outcomes are still unsatisfactory. Allogeneic stem cell transplant remains the only curative option but the majority of MDS patients are not eligible because of older age and other medical problems. Immunosuppressive therapy is helpful in a fraction of patients. Several newer agents are being tested, offering promise for the future.     

Pharmacological management of hypertensive emergencies and urgencies: focus on newer agents

Introduction: Hypertensive crises are categorized as hypertensive emergencies and urgencies depending on the presence of acute target-organ damage; the former are potentially life-threatening medical conditions, requiring urgent treatment under close monitoring. Although several short-acting intravenous antihypertensive agents are approved for this purpose, until recently little evidence from proper trials on the relative merits of different therapies was available.

Areas covered: This article discusses in brief the pathophysiology, epidemiology and diagnostic approach of hypertensive crises and provides an extensive overview of established and emerging pharmacological agents for the treatment of patients with hypertensive emergencies and urgencies.

Expert opinion: Agents such as sodium nitroprusside, nitroglycerin and hydralazine have been used for many years as first-line options for patients with hypertensive emergencies, although their potential adverse effects and difficulties in use were well known. With time, equally potent and less toxic alternatives, including nicardipine, fenoldopam, labetalol and esmolol are increasingly used worldwide. Recently, clevidipine, a third-generation dihydropyridine calcium-channel blocker with unique pharmacodynamic and pharmacokinetic properties was added to our therapeutic armamentarium and was shown in clinical trials to reduce mortality when compared with nitroprusside. In view of such evidence, a change in pharmacological treatment practices for hypertensive crises toward newer and safer agents is warranted.     

Clofarabine for myelodysplastic syndromes

Introduction: Treatment options in myelodysplastic syndromes (MDS) remain limited. The introduction of novel therapies that can improve response rates and survival outcomes in MDS remains a challenge. Clofarabine is a purine nucleoside analog that works primarily via inhibition of DNA biosynthesis and the ribonucleotide reductase enzyme with recent evidence suggesting that at low doses it may affect DNA methylation. It has been successfully used in the treatment of acute myeloid leukemia (AML) and is under investigation in MDS.

Areas covered: A PubMed search for articles pertaining to clofarabine was conducted and streamlined to only include data on MDS or AML that evolved from MDS. Also included were clofarabine-related response and safety data from presentations at the 52^nd Annual American Society of Hematology Meeting in Orlando, Florida, USA.

Expert opinion: Clinical trials using clofarabine in MDS and MDS/myeloproliferative neoplasms have produced overall response rates of 31 – 43% including complete responders. Although myelosuppression is an important side effect, clofarabine is generally well tolerated in MDS. Clofarabine is currently available in an intravenous form with an oral formulation presently under investigation, either as a single agent or in combination therapy in MDS. Larger studies may help clarify the viability of clofarabine in the treatment of MDS patients.     

Emerging treatments for urinary incontinence

Introduction: Urinary incontinence (UI) is a common and distressing problem that can adversely affect a patient's quality of life. Medical treatment is integral in the management of UI, of which there are a number of novel therapeutic targets.

Areas covered: In this review, an overview of UI and its associated burden on patients and on the healthcare system is provided. While there are many options for therapy currently available, the focus of this review is emerging therapies that may contribute in the near future to the management of UI.

Expert opinion: Healthcare expenditures for diagnosis, evaluation and treatment are substantial and are increasing as the general population ages and as access to healthcare increases. Pharmacological therapy for stress UI is limited and autologous muscle-derived cell therapy holds great promise. Despite the myriad of antimuscarinics for urge UI, all those presently FDA approved have comparable efficacy and adverse events, despite advertisements that suggest otherwise. Antimuscarinics and β agonists are likely to remain mainstays of treatment as agents that act on novel targets such as transient receptor potential vanilloid type 1 and neurokinin-1 require further study.     

Emerging drugs for the treatment of bone metastasis

Introduction: Bone metastases are virtually incurable resulting in significant disease morbidity, reduced quality of life and mortality. Bone provides a unique microenvironment whose local interactions with tumor cells offer novel targets for therapeutic interventions. Increased understanding of the pathogenesis of bone disease has led to the discovery and clinical utility of bone-targeted agents other than bisphosphonates and denosumab, currently, the standard of care in this setting.

Areas covered: In this review, we present the recent advances in molecular targeted therapies focusing on therapies that inhibit bone resorption and/or stimulate bone formation and novel anti-tumoral agents that exerts significant effects on skeletal metastases, nowadays available in clinical practice or in phase of development.

Expert opinion: New emergent bone target therapies radium-223, mTOR inhibitors, anti-androgens have demonstrated the ability to increase overall survival in bone metastatic patients, other compounds, such as ET-1 and SRC inhibitors, up to now failed to clearly confirm in clinical trials their promising preclinical data.     

Riociguat for the treatment of pulmonary hypertension: a safety evaluation

ABSTRACT

Introduction: The development of pulmonary hypertension (PH) has multifactorial underlying pathophysiological causes and can be classified into five groups. While three different classes of therapeutic drugs are licensed for the treatment of pulmonary arterial hypertension (PAH, WHO group 1), specific medical therapies are lacking for other forms of PH, such as PH due to left heart disease. In 2013 riociguat, a first-in class soluble guanylate cyclase stimulator, has also become available for the treatment of PAH. Riociguat was further introduced as the first approved pharmacotherapy for the treatment of patients with chronic thromboembolic PH (WHO group 4, CTEPH). Despite these advances in therapeutic options for patients with PH, none of these agents have been approved for the treatment of PH due to left heart disease.

Areas covered: We aim to give an overview of the pathophysiology of PH, pharmacodynamics and pharmacokinetic properties, safety and efficacy of riociguat, including adverse events, contraindications and drug interactions.

Expert opinion: Considering the increasingly broad indications for riociguat in patients with PH, substantial knowledge of data and properties on safety and efficacy of riociguat are becoming more and more important for physicians prescribing riociguat to PH patients.     

Ezatiostat hydrochloride for the treatment of myelodysplastic syndromes

Introduction: Myelodysplastic syndromes (MDSs) are associated with significant morbidity due to ineffective hematopoiesis. Given the limited number of drugs approved by the FDA, there is a need for new therapeutic options. Ezatiostat is a novel agent targeting oxidative stress via inhibition of glutathione S-transferase 1.

Areas covered: Herein, the authors summarize the standard of care in order to build the framework for therapeutic advancements. The purpose of this paper is to review the body of preclinical and clinical research literature on the investigational agent ezatiostat hydrochloride (TLK199) for the treatment of MDSs. The article includes details of the pathophysiology, pharmacology, toxicity and efficacy of ezatiostat hydrochloride from controlled studies in patients with myelodysplasia.

Expert opinion: MDS clonal heterogeneity and clonal architecture complexity has presented a significant technical challenge in developing effective therapies. Ezatiostat offers a unique and specific mechanism to improve the transfusion burden associated with myelodysplasia. Since it is tolerable as a monotherapy, combining ezatiostat with agents such as lenalidomide may have the most potential benefit.     

Immune alterations in untreated and treated myelodysplastic syndrome

Introduction: Current literature suggests a variety of immune abnormalities are present in myelodysplastic syndrome (MDS) patients. However, they have not been comprehensively characterized or systematized to date. As a result, their clinical implications remain largely unknown. In addition, an increased incidence of various autoimmune conditions has been documented in MDS patients.

Areas covered: The authors offer a comprehensive review of the existing literature on immune mechanisms involved in the pathogenesis of MDS, various immune abnormalities documented in its course, their link with the clonal evolution of MDS as well as immune alterations induced by the existing MDS therapies.

Expert opinion: The course of MDS is accompanied by complex immune alterations, including T-cell and NK-cell defects, decreased functional abilities of neutrophils and antigen-presenting cells, altered antibody and cytokine production. While contemporary MDS therapies are shown to possess some immunomodulatory properties, authentic autoimmune conditions have also been documented with lenalidomide and recombinant erythropoietin. Caution should be exerted with the use of these agents in MDS patients with evidence of autoimmune disorders, as exacerbation of autoimmune phenomena can be anticipated. While the heterogeneity of MDS represents an inherent limitation, integration of emerging information from molecular biology, genetics, immunology research and clinical practice could translate into improved outcomes of this disease spectrum.     

Safety profile of new anticancer drugs

Importance of the field: The development of targeted anticancer therapies stems from advances in molecular biology. New agents range from antibodies that form complexes with antigens on the surface of the cancer cell to small molecules that have been engineered to block key enzymatic reactions. The interaction of the antibody or drug with its target inhibits key pathways involved in cell proliferation or metastasis, or activates pathways leading to cell death. Such pathways constitute ideal pharmacological targets. Clinical benefits from these novel therapeutic strategies are striking for patients with metastatic diseases.

Areas covered: This review analyses the main toxicities among most common targeted therapies that have been approved by the FDA or European Medicines Agency for their clinical utilisation in solid tumours treatment.

What the reader will gain: Here, the main toxicity and safety data among new anticancer targeted therapies are described. Data are organised through the pathways targeted by the drugs.

Take home message: The emergence of new targeted anticancer therapies promises more efficient and less toxic therapies. Generally, they are well tolerated, toxicities are commonly mild to moderate and can be handled rapidly. However, if most of these adverse events are manageable, life threatening and fatal complications can still occur.