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.     

Evolving pharmacotherapeutic strategies for small bowel adenocarcinoma

Importance of the field: Owing to nonspecific signs and symptoms, the majority of patients with small bowel adenocarcinoma (SBA) present with advanced-stage disease. Few studies in the literature adequately address the role of chemotherapy in SBA. The regimens used in colon and gastric cancers have been tried in SBA with varying degrees of success.

Areas covered in this review: The authors explore the natural history and diagnostic evaluation of SBA, followed by a focused review of existing studies on individual agents and combinations used in the therapy of this malignancy.

What the reader will gain: 5-fluorouracil-based chemotherapy seems to offer a clinical benefit in advanced SBA. The reader will acquire considerable insights about the most effective chemotherapy drugs and combination regimens used in advanced SBA.

Take home message: Given the rarity of this malignancy, multicenter, randomized clinical trials are essential in the design of optimal therapeutic strategies for SBA. The role of adjuvant therapy in SBA remains to be clarified. Prospective evaluation of new agents and their incorporation into various therapeutic schemes for advanced/metastatic disease is also necessary. Until then, therapeutic decisions should be individualized and based on the benefits and toxicities of the most effective drugs or combinations.     

Clinical translation of folate receptor-targeted therapeutics

Introduction: Folate receptor?α (FR?α) has been established as a membrane marker for ovarian cancer. In addition, it is frequently overexpressed in other major types of epithelial tumors. FR?α-based tumor-targeted therapy and drug carriers have been an active area of laboratory research for more than 20 years. Recently, there has been a great increase in the effort to finally translate this promising technology into the clinic and bring FR-targeted therapeutics into the market.

Areas covered: Two FR-targeted therapeutic agents have moved into Phase III clinical trials, the monoclonal antibody farletuzumab and the low molecular weight vintafolide, combined with etarfolatide as a companion imaging agent, representing two alternative strategies for targeting the FR.

Expert opinion: Each of the two strategies has advantages and disadvantages. Identification of the best target patient population is likely critical to the ultimate success of FR-targeted agents in the clinic. A successful clinical strategy may require the integration between FR expression analysis and an optimal combination of FR-targeted therapy and standard chemotherapy. Advancement into Phase III trials and the ongoing clinical development of several additional folate conjugates are likely to usher in a new era of clinical translation and validation of FR-targeted imaging and therapeutic agents.     

Development of cytarabine prodrugs and delivery systems for leukemia treatment

Importance of the field: Cytarabine is a polar nucleoside drug used for the treatment of myeloid leukemia and non-Hodgkin's lymphoma. The drug has a short plasma half-life, low stability and limited bioavailability. Overdosing of patients with continuous infusions may lead to side effects. Thus, various prodrug strategies and delivery systems have been explored extensively to enhance the half-life, stability and delivery of cytarabine. Among the recent cytarabine prodrugs, amino acid conjugate ValCytarabine and fatty acid derivative CP-4055 (in Phase III trials) have been investigated for the treatment of leukemia and solid tumors, respectively. Alternatively, delivery systems of cytarabine have emerged for the treatment of different cancers. The liposomal-cytarabine formulation (DepoCyt, Pacira Pharmaceuticals Inc., New Jersey, USA) has been approved for the treatment of lymphomatous meningitis.

Areas covered in this review: Various prodrug strategies evaluated for cytarabine are discussed. Then, the review summarizes the drug delivery systems that have been used for more effective cancer therapy.

What the reader will gain: This review provides in-depth discussion of the prodrug strategy and delivery systems of cytarabine derivatives for the treatment of cancer. The design of cytarabine prodrugs and delivery systems provides insights for designing the next generation of more effective anticancer agents with enhanced delivery and stability.

Take home message: Strategies on designing cytarabine prodrug and delivery formulations showed great promise in developing effective anticancer agents with better therapeutic profile. Similar studies with other anticancer nucleosides can be an alternative approach to gaining access to more effective anticancer agents.     

Thyroid hormone replacement: current status and challenges

Introduction: Correction of hypothyroidism with synthetic levothyroxine is simple, effective and safe. In most cases levothyroxine restores well-being and normalizes serum thyrotropin (TSH) concentrations. However, up to 30 – 50% of levothyroxine users do not achieve adequate biochemical euthyroidism. Also, a small proportion of hypothyroid individuals remain dissatisfied with treatment even with normal TSH concentrations.

Areas covered: This review addresses strategies for achieving optimal thyroid hormone replacement based on a systematic search of the literature for controlled trials, cohort studies or systematic reviews published on the topic since 1960.

Expert opinion: Careful attention to factors that affect levothyroxine availability such as medication adherence, drug interactions and co-morbidities should improve the adequacy of therapy, but these factors are challenging to manage in practice. The case for combined therapy with levothyroxine and triiodothyronine (T3) is compelling but is not supported by current evidence from randomized controlled trials. Recent studies of common genetic variations in deiodinase and thyroid hormone transport proteins offer fresh insights in understanding the variable response to thyroid hormone therapy and future research may clarify whether subsets of patients will benefit from combined therapy. Despite significant challenges, opportunities abound for improving therapeutic outcomes.     

Emerging drugs for T-cell lymphoma

Introduction: T-cell lymphomas are rare and conventional treatments are not typically curative. Integration of biologic agents into routine practice is especially difficult given the breadth of emerging drugs currently or recently in trials.

Areas covered: This is an overview of the management of T-cell lymphoma as it stands today. The authors review clinically active biological and novel chemotherapeutic agents, which have a niche in current practice or are being actively developed and have a potential future role in the management of this challenging group of diseases. Clinical trial data were retrieved from journals and current major conference proceedings following interrogation of online search engines

Expert opinion: Pralatrexate, the histone deacetylase inhibitors and brentuximab vedotin have reached the market and have provided new and useful treatment options. No novel agent has yet demonstrated a survival advantage for patients with this disease, or shown an ability to improve the low response rate to first-line chemotherapy that these diseases frequently exhibit. New randomized studies of these emerging drugs that may finally move the field forward with evidence of superiority from large Phase II and III trials currently open to accrual.     

Bortezomib for the treatment of non-Hodgkin’s lymphoma

Introduction: Bortezomib, the first proteasome inhibitor (PI) to be evaluated in humans, is approved in the USA and Europe for the treatment of patients with multiple myeloma, and in the USA for patients with relapsed mantle cell lymphoma (MCL).

Areas covered: This review examines the role of bortezomib in the therapy of non-Hodgkin’s lymphoma (NHL). Bortezomib may be particularly effective against the NF-κB-dependent activated B-cell subtype of diffuse large B-cell lymphoma. The combination of bortezomib with rituximab and dexamethasone represents a standard approach for the treatment of Waldenström’s macroglobulinemia, and that with bendamustine and rituximab has demonstrated excellent efficacy in follicular lymphoma. Combinations with other novel agents, such as inhibitors of cyclin-dependent kinases or histone deacetylases, also hold substantial promise in NHL. Unmet needs in NHL, competitor compounds, chemistry, pharmacokinetics, pharmacodynamics and safety and tolerability of bortezomib are also discussed.

Expert opinion: The success of bortezomib in MCL has validated the proteasome as a therapeutic target in NHL. Rational combinations, for example, with Bruton’s tyrosine kinase inhibitors or BH3-mimetics, may hold the key to optimizing the therapeutic potential of PIs in NHL. Future trials are likely to involve newer agents with improved pharmacodynamic (e.g., carfilzomib, marizomib) or pharmacokinetic (e.g., ixazomib, oprozomib) properties.     

Treatment of the patient with diabetes: importance of maintaining target HbA1c levels

SUMMARY

Objective: To review clinical trial evidence supporting treatment of patients to a near-normal HbA_1c target level and outline therapeutic strategies that optimize glycemic control.

Research design and methods: The current MEDLINE database and bibliographies were searched for literature relevant to diabetic complications, glycemic control, and the intensive management of diabetes mellitus.

Results: Two randomized trials, the Diabetes Control and Complications Trial and the UK Prospective Diabetes Study (UKPDS), provided evidence that intensive glycemic control obtained with either intensive insulin or oral therapy effectively slowed the onset and progression of diabetic retinopathy, nephropathy, and neuropathy in patients with type 1 and type 2 diabetes. An epidemiologic analysis of the UKPDS results showed a significant correlation between glycemic control and microvascular and cardiovascular disease risk and mortality rates.

Conclusions: The results of clinical trials confirm that stringent levels of glycemic control can be attained through the use of intensive multiple-injection insulin regimens (administration of insulin 3 or more times daily by injection or an external pump with dosage adjustments as needed), oral monotherapy or combination therapy, or a combination of insulin and oral therapy. The expanded choices for oral agents and the availability of insulin analogs now provide physicians with the tools to tailor therapy to prevent or delay the devastating complications of diabetes. Indeed, newer insulin analogs, both short-acting (insulin lispro, insulin aspart) and long-acting (insulin glargine), are an important part of a treatment strategy to circumvent diabetes complications and overcome the shortcomings of conventional insulin preparations.     

The expanding role of nilotinib in chronic myeloid leukemia

Importance of the field: Several therapeutic options, including tyrosine kinase inhibitors, exist for the treatment of patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Despite impressive results, there is room for improvement for those patients who are either resistant or intolerant to imatinib.

Areas covered in this review: An overview is given on the clinical results with nilotinib, a rationally designed second-generation tyrosine kinase inhibitor, as first- and second-line therapy in patients with Ph-positive CML. Important factors in predicting resistance to nilotinib and guiding therapeutic decisions are addressed.

What the reader will gain: Knowledge on the clinical efficacy and safety of nilotinib after imatinib failure and as first-line treatment. Point mutations in the kinase domain (KD) of BCR-ABL1 are important determinants of clinical sensitivity to currently available tyrosine kinase inhibitors, including nilotinib. Information on specific BCR-ABL1 KD mutations and safety profiles assist in therapeutic decision making.

Take home message: Nilotinib is a highly effective and well-tolerated therapeutic option in patients with Ph-positive CML after imatinib failure. Early evidence demonstrating increased efficacy has allowed expanding nilotinib to previously untreated patients in chronic phase. Insights into mechanisms of resistance to tyrosine kinase inhibitors and predictive factors for response will allow for a more individualized use of these agents.     

Challenges and advances in the development of inhalable drug formulations for cystic fibrosis lung disease

Introduction: Cystic fibrosis (CF) is a multisystem genetic disorder, which usually results in significant respiratory dysfunction. At present there is no cure for CF, but advances in pharmacotherapy have gradually increased the life expectancy of CF patients. As many drugs used in the therapy of CF are delivered by inhalation, the demand for effective and convenient inhalational CF drug formulations will grow as CF patients live longer. Knowledge of the current limitations in inhalational CF drug delivery is critical in identifying new opportunities and designing rational delivery strategies.

Areas covered: This review discusses current and emerging therapeutic agents for CF therapy, selected physiological challenges to effective inhalational medication delivery, and various approaches to overcoming these challenges. The reader will find an integrated view of the known inhalational drug delivery challenges and the rationales for recent investigational inhalational drug formulations.

Expert opinion: An ideal drug/gene delivery system to CF airways should overcome the tenacious sputum, which presents physical, chemical and biological barriers to effective transport of therapeutic agents to the targets and various cellular challenges.     

Emerging role of the histone deacetylase inhibitor romidepsin in hematologic malignancies

Importance of the field: Histone acetylation plays a crucial role in chromatin modification and the regulation of gene expression. Histone deacetylase inhibitors (HDACi) are a novel class of antitumor agents with pleiotropic effects; they are under active clinical investigation. The HDACi romidepsin is being evaluated in a variety of tumors and was recently approved for the treatment of cutaneous T-cell lymphomas (CTCL).

Areas covered in this review: This review focuses on the findings from early Phase trials involving romidepsin, and the Phase II trial results that led to the approval of romidepsin in CTCL.

What the reader will gain: Mechanisms of action of HDACi, including romidepsin, are described in this review and the pharmacodynamic and pharmacokinetic properties of romidepsin are summarized. The efficacy and safety profile of romidepsin in clinical trials in T-cell lymphoma is reviewed, and emerging data on single-agent and combination strategies in myeloid and B-lymphoid malignancies is outlined.

Take home message: Romidepsin has significant activity and an acceptable safety profile in CTCL and peripheral T-cell lymphomas. Its use in rationally designed combination approaches is under active investigation in B-lymphoid malignancies.     

Emerging therapeutic options for advanced enteropancreatic neuroendocrine tumors

Introduction: Several chemotherapy agents and combinations have proven effective in the therapy of advanced enteropancreatic neuroendocrine tumors (EP-NETs). However, their toxicity can be significant. Recent understanding of the molecular mechanisms of these tumors, especially the central role of tumor angiogenesis, has led to the identification of new therapeutic targets and agents directed at the molecular level.

Areas covered: This paper gives a comprehensive evaluation of the existing therapeutic armamentarium for EP-NETs. Narrated in a historical perspective, this review analyzes the available information on traditional chemotherapy agents, interferon-α and somatostatin analogs, as well as newer therapies and experimental agents.

Expert opinion: Despite recent advances, a curative approach for metastatic EP-NETs is yet to be discovered. To date, sunitinib and everolimus have been shown to impact progression-free survival only in pancreatic NETs, and the duration of this benefit has not yet been established. Further research is necessary to determine whether a combination of these drugs, either together or with other therapies, may yield superior outcomes. Moreover, sequential use of these agents should be explored in an attempt to improve survival. Efficacy of a variety of experimental agents is also being tested in clinical trials.     

Insulin and GLP-1 analog combinations in type 2 diabetes mellitus: a critical review

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists have been used in clinical management of type 2 diabetes since 2005. Currently approved agents were initially developed and approved for combination therapy with oral antidiabetic drugs (OADs). The potential for combined use with insulin has garnered increasing attention due to the potential to reduce side effects associated with insulin therapy and improve glycemic control.

Areas covered: We reviewed published and other publicly released data from controlled and uncontrolled studies that included subjects treated with insulin/GLP-1 analog combination therapy. The currently available guidance for clinical practice when combining insulin and GLP-1 analogs was also summarized.

Expert opinion: Limited data currently available from placebo-controlled trials support the use of exenatide twice daily or liraglutide once daily in combination with basal insulin and metformin in subjects with type 2 diabetes unable to attain treatment goals. Several randomized controlled trials are currently studying combinations of insulin with various GLP-1 analogs. Additional guidance on the clinical use of these combinations will likely be forthcoming once these studies are reported. Insulin/GLP-1 analog combinations will require optimization of blood glucose monitoring strategies and delivery systems to decrease the risk of administration errors and reduce the potential complexity of these regimens.     

Protein kinase inhibitors to treat non-small-cell lung cancer

Introduction: Activating mutations of the EGFR and rearrangement of anaplastic lymphoma kinase (ALK) best illustrate the therapeutic relevance of molecular characterization in NSCLC patients.

Areas covered: For this review article, all published data on the most relevant Phase III trials with tyrosine kinase inhibitors (TKIs) for the treatment of NSCLC were collected and analyzed.

Expert opinion: Eight Phase III trials clearly established EGFR TKIs as the best therapeutic option for front-line therapy in EGFR-mutated patients. In pretreated NSCLC, EGFR TKIs are considered more effective than standard monotherapy with cytotoxics in presence of classical EGFR mutations, whereas in the EGFR wild-type population, a similar efficacy to docetaxel or pemetrexed in term of survival has been demonstrated. In ALK-translocated NSCLC, a Phase III trial demonstrated the superiority of a multi-target TKI, including ALK, in terms of progression-free survival, response rate and toxicity profile when compared to standard second-line chemotherapy. New agents targeting EGFR or ALK are under evaluation particularly in individuals with acquired resistance to EGFR TKIs or crizotinib.     

Treatment approaches for primary CNS lymphomas

Importance of the field: Primary central nervous system lymphomas (PCNSL) are rare but potentially curable tumours. The overall outcome for PCNSL patients is unsatisfactory and several therapeutic questions remain open. Modest progress in outcome reflects difficulties in conducting randomized trials and scarce molecular and biological knowledge.

Areas covered in this review: This review describes conventional and investigational treatments for PCNSL and focuses on the main questions for future clinical trials. PubMed and the authors’ own files were utilized for references search. The terms ‘PCNSL’, ‘primary AND CNS lymphoma’, and ‘CNS AND lymphoma’ were used for PubMed queries. All papers published in English before November 2009 were considered.

What the reader will gain: This review illustrates how the paradigm for PCNSL treatment changed during the 1990s from radiotherapy alone to the establishment of high-dose methotrexate–cytarabine combination as standard approach. We present promising data from Phase II studies and discuss questions for randomized trials. Finally, we offer a 5-year scenario for the management of PCNSL.

Take-home message: The methotrexate–cytarabine combination should currently be considered as the reference treatment for PCNSL. Well-designed randomized trials and biological studies deriving from the use of novel technologies will be crucial to further improve outcome in these patients.     

Pharmacotherapeutic management of autism

Importance of the field: Acute promyelocytic leukemia (APL) represents a paradigm of therapeutic success in clinical hematology. Since the introduction of all-trans-retinoic-acid in the early 1980s, complete remission rates exceed 90% and the cure rate is >?70%. Notwithstanding, various questions concerning the management of APL remain unanswered.

Areas covered in this review: The aim of this article is to focus on still controversial issues in the management of APL, such as the role of arsenic trioxide as front-line therapy, the management of older unfit patients, the potential utility of gemtuzumab–ozogamycin and the effectiveness (if any) of maintenance therapy for patients in molecular remission. In addition, the possibility of reducing the intensity of post-remission therapy, which is associated with substantial morbidity in potentially cured patients, is discussed.

What the reader will gain: Current and future therapeutic options for the treatment of newly diagnosed and relapsed APL.

Take home message: To date, the therapy of APL is the most successful example of differentiation therapy and its scientific history can serve as a model for subsequent development of similar treatments in other leukemias and cancers. However, treatment strategies continue to evolve rapidly, with particular focus on minimizing the early and late effects of cytotoxic chemotherapy.     

PCI-32765: a novel Bruton's tyrosine kinase inhibitor for the treatment of lymphoid malignancies

Introduction: There has been a significant paradigm shift in the manner in which lymphoid malignancies are treated and managed. Treatment has been moving away from conventional chemotherapy and towards targeted therapy. The success of new classes of agents such as monoclonal antibodies, proteasome inhibitors and immunomodulatory derivatives has sparked further searches for novel pathways to inhibit. The Bruton's tyrosine kinase (Btk) pathway is a downstream mediator of the B-cell receptor (BCR) pathway, which is crucial in B-cell production and maintenance, and a potential therapeutic target.

Areas covered: This review will summarize the current knowledge of the Btk pathway and its role in lymphoid malignancies. It will also discuss the present data about PCI-32765 in both the preclinical and clinical setting.

Expert opinion: PCI-32765 is an oral irreversible Btk inhibitor with high potency and both preclinical and clinical activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). Phase I studies have demonstrated that it is well tolerated and has an excellent safety profile. Further studies are ongoing as a single agent and in combination with other targeted and conventional therapies. PCI-32765 is a very promising targeted therapy, and the data from these trials will ultimately decide its future role and success.     

Blinatumomab for the treatment of B-cell lymphoma

Introduction: Blinatumomab is a bispecific T-cell engager (BiTE) molecule that recruits cytotoxic T cells to target tumor B cells by linking the CD3 and CD19 antigens. Among the various formats of bispecific antibodies developed in the past 50 years, the BiTE class is remarkable for its low effector-to-target ratio, high tissue penetration and singular ability to activate T cells independent of MHC class I presentation or costimulation. Blinatumomab has been studied in patients with relapsed or refractory non-Hodgkin’s lymphoma (NHL) and B-precursor acute lymphoblastic leukemia (B-ALL).

Areas covered: This article reviews the current literature on blinatumomab including its pharmacology, preclinical findings, clinical trials in B-cell NHL and, to a lesser extent, Phase II studies in B-ALL. The authors discuss the potential future directions in light of other new competing therapies for NHL and unmet clinical needs in the market.

Expert opinion: The recent approval of blinatumomab for B-ALL symbolizes a breakthrough for BiTE technology with prospective application in the targeted therapy of other cancers. Although blinatumomab seems an unlikely option for treating indolent lymphoma due to toxicity, the need for long-term continuous infusion therapy and multiple promising well-tolerated oral agents, it holds promise for aggressive NHL patients whose diseases are refractory to current standard approaches. Larger trials are needed to demonstrate blinatumomab’s curative potential in aggressive histologies.     

In pursuit of a moving target: nanotherapeutics for the treatment of non-Hodgkin B-cell lymphoma

Introduction: Non-Hodgkin lymphoma (NHL) is diagnosed in 70,000 Americans annually. Chemotherapy was the standard course of treatment until the addition of the monoclonal antibody (mAb) drug, rituximab, to therapy regimens in 1997. Although disease prognosis has improved dramatically since that time, nearly 20,000 patients succumb annually to the disease, with an average life expectancy beyond diagnosis of only 12 years. The advent of nanomedicine may fulfill the remaining need for novel therapy capable of eradicating solid tumor and disseminated B-cell lymphomas.

Areas covered: This review details the current landscape of B-cell NHL and nanoparticles now being developed for its treatment. Specifically, we discuss lipid, polymer and metal nanoparticles that deliver an array of drugs, including toxins, chemotherapeutic agents and nucleic acids.

Expert opinion: Because B-cell malignancies have responded quite well to new components in multi-drug regimens, nanomedicines that are mechanistically distinct from existing therapies hold significant promise. In our opinion, advancement of these technologies into the clinic will likely require significantly more effective targeting systems coupled with a better understanding of lymphoma biology. Furthermore, it is important for researchers to recognize the genetic and phenotypic heterogeneity of NHL and to develop therapeutic strategies for distinct subsets of NHL before attempting to generalize approaches.     

Pharmacogenomics of pediatric acute lymphoblastic leukemia

Importance of the field: Pediatric acute lymphoblastic leukemia (ALL) represents one of the best examples of progress in disease treatment and improved outcome based in part upon the incorporation of the principles of pharmacogenomics. Throughout the past several decades, clinical scientists have continued to refine risk stratification in clinical trials with the understanding that individual patients have different subtypes of pediatric ALL that will respond to therapy in different, but predictable ways.

Areas covered in this review: Discussed in this review are the most significant findings from pharmacogenomic studies of pediatric ALL from 1989 to the present. Pharmacogenomic studies related to the drugs commonly used to treat pediatric ALL are covered in detail, including an emphasis on both genome-wide and candidate gene/pathway approaches.

What the reader will gain: Readers of this paper will acquire a detailed understanding of how pharmacogenomic studies can be integrated into clinical trials, in addition to some of the discrepancies still present in the field.

Take home message: The outcome for children with pediatric ALL has improved greatly, and this is in part due to the successful integration of data from pharmacogenomic studies into clinical trials.