Forodesine in the treatment of cutaneous T-cell lymphoma

Introduction: Cutaneous T-cell lymphoma (CTCL) is characterized by the accumulation of neoplastic CD4+ T lymphocytes in the skin. Given the lack of curative treatments for CTCL, there is a significant need for new, superior therapies. Forodesine is a transition-state analogue that inhibits purine nucleoside phosphorylase. Because it selectively targets T lymphocytes, it represents a drug of interest for the treatment of CTCL.

Areas covered: Phase I/II dose-ranging studies of intravenous (IV) and oral forodesine demonstrated its activity, safety, and tolerability for refractory CTCL. Response rates were 31% and 27%, respectively. No dose-limiting toxicities were observed. These studies were followed by a phase II trial of oral forodesine 200 mg daily. This oral formulation showed only partial activity, with a response rate of 11%, likely attributable to underdosing. Common adverse events in these trials included infection, fatigue, peripheral edema, nausea, pruritus, headache, and insomnia.

Expert opinion: IV and oral formulations of forodesine have demonstrated partial activity and an acceptable safety profile in patients with refractory CTCL. A higher oral dose, or sequential therapy consisting of IV forodesine followed by maintenance oral forodesine, may be more effective. With proper dosing, forodesine may emerge as a safe and effective treatment for refractory CTCL.     

Mechlorethamine gel for the topical treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma

Mycosis fungoides (MF) is an extranodal non-Hodgkins lymphoma of T-cell origin. MF is the most common type and can be stratified as early (IA-IIA) or late (IIB or greater) stage disease. Patients with patch disease usually have a benign, chronic course. Patients with plaques have a worse prognosis and need more aggressive therapy. Topical nitrogen mustard ([NM]; mechlorethamine hydrochloride) has been used for MF since the 1950s. Complete response rates reported for stage IA are 76–80% and 35–68% for stage IB. Most common toxicities reported are irritant contact dermatitis, allergic reaction and hyperpigmentation. There is a potential for risk of non-melanoma skin cancers reported with NM use in patients who used multiple skin damaging therapies. This article focuses on the clinical trial that led to the US FDA approval of VALCHLOR? for stage IA and IB MF in 2013 after one prior treatment (excluding NM within 2 years or carmustine therapy ever).     

IPH4102, a monoclonal antibody directed against the immune receptor molecule KIR3DL2, for the treatment of cutaneous T-cell lymphoma

Introduction: Therapeutic options for mycosis fungoides and Sézary syndrome include a variety of immunomodulatory, epigenetic, and cytotoxic options; however, none has been demonstrated to be efficacious for all patients, or to deliver deep and durable responses to the majority of patients. In this review, we examine the monoclonal antibody, IPH4102, a novel agent for the treatment of cutaneous T-cell lymphoma.

Areas covered: In this review, we examine data demonstrating the tissue specificity of KIR3DL2 receptor, which is highly expressed on the malignant cells in cutaneous T-cell lymphoma, including mycosis fungoides and Sézary syndrome. This specificity has led to the development of the agent IPH4102. Preclinical data showing efficacy of IPH4102 in vivo are outlined, as well as the results from Phase I clinical trials, which suggest that the agent is both efficacious and well-tolerated. Larger scale clinical trials are to follow.

Expert Opinion: We examine the putative benefit of IPH4102 in comparison to established agents already in the clinic, highlighting its efficacy and relative safety. We also examine possible directions that may better define the role of IPH4102 in the treatment of T-cell lymphoma in the future.     

The discovery and development of romidepsin for the treatment of T-cell lymphoma

Introduction: Romidepsin is a potent and selective inhibitor of histone deacetylases (HDCAi). It is also the only bicyclic inhibitor to undergo clinical assessment and is considered a promising drug for the treatment of T-cell lymphomas. The cellular action of romidepsin results in enhanced histone acetylation, as well as the acetylation of other nuclear or cytoplasmic proteins, influencing cell cycle, apoptosis, and angiogenesis. In phase II studies involving patients with relapsed or refractory of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), romidepsin produced overall response rates (ORR) of 34–35% and 25–38%, with complete response (CR) rates of 6% and 15–18%, respectively.

Areas covered: This review summarizes the development of romidepsin, the mechanisms behind its antineoplastic action and its pharmacology. It also covers its pharmacokinetic and pharmacodynamic properties, as well as the preclinical and clinical data on its activity in T-cell lymphoma.

Expert opinion: Since there are only few effective therapies available for T-cell lymphomas, romidepsin is a valuable option for relapsed/refractory patients with both CTCL and PTCL. It’s also generally well tolerated, and gives potentially durable responses for patients with advanced and symptomatic disease. Combinations of romidepsin with other antineoplastic agents may also further improve drug response and outcomes in T-cell lymphoma.     

Bexarotene in the treatment of cutaneous T-cell lymphoma

Primary cutaneous T-cell lymphomas encompass a spectrum of non-Hodgkin’s lymphomas that are characterised by clonal proliferation of skin-homing malignant T lymphocytes. Mycosis fungoides and the leukaemic variant Sézary syndrome, collectively referred to as cutaneous T-cell lymphomas, are the most common entities. No curative therapy exists and patients ultimately develop advanced or relapsed disease that is refractory to standard treatment options. Therefore, there is a great need for the development of novel emerging therapies. Bexarotene is the first synthetic nuclear retinoid X receptor-selective retinoid approved by the FDA for the treatment of refractory cutaneous T-cell lymphoma in all stages, as both an oral capsule and a topical gel formulation. Bexarotene was found to induce apoptosis in a variety of preclinical in vitro and in vivo models including cutaneous T-cell lymphoma cells, and has shown efficacy in two multi-centre, open-label Phase II – III clinical trials for early and advanced stages of cutaneous T-cell lymphoma in patients who have failed or were refractory to standard therapies. New insights into the immunomodulatory function of bexarotene have indicated opportunities for combined treatment with IFN-α, denileukin diftitox or phototherapy. This article reviews the biological properties, pharmacokinetics, clinical efficacy, safety and role of bexarotene in the treatment of cutaneous T-cell lymphoma.     

Bexarotene in cutaneous T-cell lymphoma: third retrospective study of long-term cohort and review of the literature

Background: Bexarotene was approved for cutaneous T-cell lymphoma (CTCL) in 1999. Apart from the two first clinical trials published ten years ago, very few data were published on the long-term use of bexarotene in CTCL patients.

Objectives: We performed a retrospective review of CTCL patients treated with bexarotene at a single skin Cancer department between 2002 and 2012. We aimed to determine retrospectively the long-term tolerability and outcome of bexarotene in a cohort of CTCL patients and to compare these results with data from the literature.

Results: Thirty-two patients were included (18 men/14 women); 20 patients had a mycosis fungoïdes and 12 a Sézary syndrome. The longest bexarotene treatment duration observed was 65.2 months and 10 patients were treated for more than 24 months. A clinical response was reported in 60% of all patients and in 75% of patients with Sézary syndrome. Most common drug-related adverse events were hypothyroidism (94%), hypertriglyceridemia (78%) and hypercholesterolemia (44%). Most events (84%) were mild to moderate.

Conclusions: This study with a very long observation time confirms that bexarotene is well tolerated by CTCL patients during long-term use. It is effective in early and advanced stages of CTCL.     

A safety evaluation of brentuximab vedotin for the treatment of Hodgkin lymphoma

ABSTRACT

Introduction: Brentuximab vedotin is an anti-CD30 monoclonal antibody-drug conjugate approved for treating relapsed or refractory Hodgkin lymphoma. The pivotal trial demonstrated brentuximab vedotin’s efficacy and manageable toxicity profile with peripheral neuropathy and neutropenia being the most common side effects. The phase I study of brentuximab vedotin combined with ABVD or AVD revealed its contraindication with bleomycin due to pulmonary toxicity. As trials continue to investigate the drug in frontline and relapsed settings, emerging safety data will further define brentuximab vedotin’s role in managing Hodgkin lymphoma.

Areas covered: This article reviews the current literature on brentuximab vedotin in Hodgkin lymphoma treatment, both as a single agent and in combination regimens. The review focuses on safety findings from clinical trials, expected adverse events, and rare serious toxicities.

Expert opinion: Brentuximab vedotin is a breakthrough antibody-drug conjugate that may provide new options in earlier lines of therapy for Hodgkin lymphoma. Results from the ongoing phase III trial comparing ABVD to AVD + brentuximab vedotin will inform whether brentuximab vedotin adds benefit to frontline therapy over the current standard of care. The optimal duration of treatment and brentuximab vedotin’s potential as an alternative to radiation in early stage disease still warrant investigation.     

外周T细胞淋巴瘤治疗新药普拉曲沙的药理及临床评价

普拉曲沙为首个治疗外周T细胞淋巴瘤(peripheral T-cell lymphoma,PTCL)药物,适用于复发或对其他化疗药物治疗无效的PTCL患者。本文通过检索文献,对普拉曲沙的作用机制、药动学、药理作用、临床评价及不良反应等方面进行了综述,为临床用药提供参考。     

皮肤T细胞淋巴瘤治疗新药伏立诺他

伏立诺他是一种新型的分子靶向抗肿瘤药物,通过抑制组蛋白去乙酰基酶(histone deacetylase,HDAC)而使细胞周期停滞和/或细胞凋亡。它是美国FDA批准的第一个用于治疗经两个全身治疗方案后仍进展、耐药或复发的具有明显皮肤侵犯的皮肤T细胞淋巴瘤(CTCL)的HDAC抑制剂。文中概述了其药理毒理、药动学、不良反应、注意事项和药物相互作用等方面的内容。     

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.     

Investigative drugs for the treatment of cutaneous T-cell lymphomas (CTCL): an update

Introduction: Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of skin-homing T-cell neoplasms, which represent approximately 75% of all primary cutaneous lymphomas. Mycosis fungoides and Sézary syndrome are the most common CTCL. Early stage disease follows a protracted course, carries a 5-year disease specific survival of 97% and can be treated with skin-directed therapies. Widespread, advanced disease has a 5-year OS of less than 25% and necessitates systemic treatment. Allogeneic stem cell transplantation is a potentially curative treatment option for advanced CTCL, however, transplant-related morbidity and mortality must be considered and a risk-benefit assessment performed on individual basis.

Areas covered: Herein, we provide a review of investigative drugs in early-stage trials for the treatment of cutaneous CTCL, including topically applied immunomodulators such as replicating herpes virus or toll-like receptor 7/8 agonist resiquimod and systemic therapies with monoclonal antibodies, such as anti-CD47, recombinant cytotoxic interleukin 2 fusion protein anti-KIR3DL2 antibody and anti-miR-155 antibody.

Expert Opinion: Among the reviewed drugs, resiquimod shows promising clinical efficacy with good tolerability in early CTCL. In refractory or relapsed disease, intratumoral anti-CD47-, anti-CCR4- and anti-KIR3DL2-antibodies show high response rates, however, latter two also show considerable toxicity. Larger trials are needed to better evaluate the discussed therapies.     

Pixantrone: a novel anthracycline-like drug for the treatment of non-Hodgkin lymphoma

Introduction: The current treatment approach of high-grade non-Hodgkin lymphoma (NHL) relies to a large extent on anthracycline-based regimens yielding cure rates in ～ 65 – 75% of patients. Despite being highly effective, these regimens are associated with significant long-term toxicity with a cumulative 10-year incidence of cardiovascular disease of 22%. Moreover, for the 25 – 35% of patients who fail first-line therapy there has been very little progress in terms of salvage regimens over the past 15 years. Re-treatment with anthracyclines-based regimens was, until now, not an option given the extensive cardiac toxicity of these agents. Pixantrone dimaleate (Pixantrone) is a novel anthracycline-like drug that offers an interesting alternative for the treatment of aggressive NHL.

Areas covered: This article provides an overview of treatment-related cardiac toxicity in NHL, the pharmacology of Pixantrone and the evidence supporting its use in NHL.

Expert opinion: Pixantrone is a potential alternative agent with a favorable safety profile for the treatment of relapsed and refractory NHL patients. It might benefit from combinations strategies and further development in the elderly and frail population.     

Alogliptin for the treatment of type 2 diabetes: a drug safety evaluation

ABSTRACT

Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors such as alogliptin are becoming more widely established as treatment options for patients with type 2 diabetes (T2DM) because of their ability to improve glycemic control without increasing the risk of hypoglycemia or weight gain. New therapies with improved safety profiles are needed, especially because of the chronic and progressive nature of T2DM.

Areas covered: In this article, the overall safety and tolerability of alogliptin are evaluated based upon a review of the literature. In particular, adverse events (AEs) that have been of interest for the DPP-4 class of drugs, such as the risk of major cardiovascular (CV) events and acute pancreatitis, will be investigated in detail.

Expert opinion: Alogliptin is generally well-tolerated in a broad range of patient populations including different ethnic groups and the elderly. In the pivotal EXAMINE clinical trial, alogliptin was found not to be associated with an increased risk of major CV events or acute pancreatitis/pancreatic cancer.     

Linagliptin for the treatment of type 2 diabetes mellitus: a drug safety evaluation

Introduction: Established treatments for type 2 diabetes mellitus (T2DM) have side effects that limit their use in specific populations. New therapies with improved safety profiles are needed, especially because of the chronic and progressive nature of T2DM.

Areas covered: This review describes the overall safety and tolerability of linagliptin – a dipeptidyl peptidase-4 inhibitor that improves glycemic control without increasing risk for hypoglycemia and without weight gain. Specifically, the safety of linagliptin is evaluated in difficult-to-treat patients with T2DM, in relation to risk of cardiovascular (CV) events and acute pancreatitis, and in comparison with other antihyperglycemic drugs.

Expert opinion: Linagliptin is generally well tolerated in a broad range of patient populations. It can be used in patients with renal impairment without dose titration and may be a rational alternative treatment in this vulnerable population. Ongoing long-term trials are fully evaluating the CV and renal safety profile of linagliptin.     

利妥昔单抗对于非霍奇金淋巴瘤的治疗及其药物经济学

目的:阐述利妥昔单抗对于非霍奇金淋巴瘤的疗效和药物的不良反应,并尝试探讨其药物经济学。方法:借鉴国外的研究并结合本院血液科对于这方面的探索,采用非传统的药物经济学模式来评价利妥昔单抗的治疗方案。结果:从药物经济学的角度而言,利妥昔单抗联合环磷酰胺 多柔比星(阿霉素) 长春新碱 泼尼松(CHOP)方案治疗非霍奇金淋巴瘤较传统单用CHOP方案优势明显。结论:利妥昔单抗具有较好的疗效和安全性,也是治疗非霍奇金淋巴瘤较经济的方法。     

信迪利单抗联合DA-EPOCH-R方案治疗弥漫大B细胞淋巴瘤的效果及安全性评价

目的 评价信迪利单抗联合环磷酰胺＋表柔比星＋依托泊苷＋长春新碱＋泼尼松、利妥昔单抗无放射治疗（DA-EPOCH-R）方案治疗弥漫大B细胞淋巴瘤（DLBCL）的效果及安全性。方法 回顾性选取2019年3月—2022年2月洛阳市第三人民医院收治的经一线治疗方案治疗后疾病复发或进展的DLBCL患者103例,根据治疗方案分为试验组54例、对照组49例。对照组给予DA-EPOCH-R方案治疗,试验组在对照组基础上加用信迪利单抗治疗。比较两组治疗前后免疫相关指标、血管内皮生长因子（VEGF）、血清胸苷激酶1（TK1）、白细胞介素-2（IL-2）水平,统计疗效和不良反应。结果 试验组客观缓解率（ORR）达72.22%,高于对照组的53.06%,差异有统计学意义（P<0.05）。治疗后,试验组Treg细胞占比及VEGF、TK1水平低于本组治疗前（P<0.05）,Th17细胞占比、IL-2水平高于本组治疗前（P<0.05）;对照组NK细胞占比及VEGF、TK1水平低于本组治疗前（P<0.05）,Treg细胞占比及IL-2水平高于本组治疗前（P<0.05）;两组CD3⁺T、CD3⁺CD4⁺T、CD3⁺CD8⁺T与治疗前比较无统计学意义（P>0.05）。试验组治疗后IL-2水平、NK细胞占比、Th17细胞占比较对照组更高（P<0.05）,Treg细胞占比及VEGF、TK1水平较对照组更低（P<0.05）。试验组和对照组败血症、皮疹、肺部感染、黏膜炎、腹泻、恶心呕吐、脱发、肾功能损伤、肝功能损伤、血小板减少、白细胞减少、贫血、发热、甲状腺功能减退等不良反应方面比较,差异无统计学意义（P>0.05）。结论 信迪利单抗联合DA-EPOCH-R方案治疗DLBCL可改善患者免疫功能,降低VEGF、TK1的表达,加强疗效,安全性良好。     

Idelalisib for the treatment of non-Hodgkin lymphoma

Introduction

B-cell Non-Hodgkin lymphomas (B-NHLs) include a number of disease subtypes, each defined by the tempo of disease progression and the identity of the cancerous cell. Idelalisib is a potent, selective inhibitor of the delta isoform of phosphatidylinositol-3-kinase (PI3K), a lipid kinase whose over-activity in B-NHL drives disease progression. Idelalisib has demonstrated activity in indolent B-NHL (iB-NHL) and is approved for use as monotherapy in patients with follicular lymphoma and small lymphocytic lymphoma and in combination with rituximab in patients with chronic lymphocytic leukemia.

Areas Covered

Herein we review the development and pharmacology of idelalisib, its safety and efficacy in clinical studies of iB-NHL, and its potential for inclusion in future applications in iB-NHL and in combination with other therapies.

Expert Opinion

Idelalisib adds to the growing arsenal of iB-NHL pharmacotherapeutics and to the progression of the field toward precision agents with good efficacy and reduced toxicities. Nevertheless, idelalisib carries important risks that require careful patient counseling and monitoring. The appropriate sequencing of idelalisib with other proven treatment options in addition to its potential for combination with established or novel drugs will be borne out in ongoing and planned investigations.     

Tiotropium for the treatment of asthma: a drug safety evaluation

ABSTRACT

Introduction: Tiotropium, a once-daily long-acting anticholinergic bronchodilator, has recently been approved for use in the treatment of asthma in a number of countries, including the EU and the USA, and was incorporated into the 2015 update of the Global Initiative for Asthma treatment guidelines. Here we review safety data from published clinical trials to help inform the use of tiotropium in the treatment of patients with asthma.

Areas covered: Safety data from recently published clinical trials, which compared tiotropium with placebo or an active control, were reviewed. Trials included children, adolescents, and adults across severities of symptomatic asthma, and assessed tiotropium delivered via the Respimat and HandiHaler devices.

Expert opinion: Based on the reviewed scientific evidence, tiotropium is a safe and well-tolerated long-acting anticholinergic bronchodilator for use in the treatment of asthma. In the trials assessed, the safety of tiotropium was found to be comparable with that of placebo and alternative therapeutic options, including a doubling in the dose of inhaled corticosteroids and the long-acting β₂-agonist salmeterol.     

A drug safety evaluation of risankizumab for psoriasis

ABSTRACT

Introduction: Risankizumab is a fully human monoclonal antibody that selectively targets interleukin (IL)-23A, interfering with the IL-23/17 axis that plays a crucial role in keratinocyte proliferation. In 2019, risankizumab was approved globally for the treatment of moderate-to-severe psoriasis.

Areas covered: The safety profile of risankizumab for the treatment of psoriasis is assessed in this review. A literature search was performed on 18 October 2019, and additional data from pooled safety analyses were evaluated.

Expert opinion: Drugs blocking the IL-23 pathway are the most recently approved treatment for psoriasis, and risankizumab seems to be the most effective one among the three IL-23 blockers approved. Risankizumab was generally well tolerated in the clinical trials and was found to be relatively safe. The safety profile of risankizumab is generally similar in clinical trials compared to adalimumab and ustekinumab. In a subset of patients with latent tuberculosis, no active tuberculosis developed after risankizumab treatment for 55 weeks without tuberculosis prophylaxis. The combination of safety, efficacy and less frequent injection (every 12 weeks) make risankizumab an attractive new choice for individuals with moderate-to-severe psoriasis. However, the long-term impact of anti-drug antibodies (24%) observed in pivotal studies as well as safety concerns in those with viral infections, hepatitis, malignancies and those in endemic tuberculosis areas, await further studies.     

Nano-based antileishmanial agents: A toxicological study on nanoparticles for future treatment of cutaneous leishmaniasis

Cutaneous leishmaniasis (CL) is endemic in the tropical and subtropical countries. Antileishmanial drugs that are traditionally used for treatment of CL are mainly toxic, ineffective for some parasite isolates, and mostly expensive. Previous studies showed that some metal and metal oxide nanoparticles have antimicrobial activity. Moreover, the use of nanoparticles together with ultra violet (UV) and infra red (IR) light increases toxic effects of nanoparticles by generation of reactive oxygen species (ROSs) and heat, respectively. There is little information on antileishmanial activity of nanoparticles, alone or together with UV/IR. Thus, the purpose of this research was to study antileishmanial effects of some nanoparticles including silver nanoparticles (Ag NPs), gold nanoparticles (Au NPs), titanium dioxide nanoparticles (TiO₂ NPs), zinc oxide nanoparticles (ZnO NPs), and magnesium oxide nanoparticles (MgO NPs) on Leishmania major parasites under UV, IR, and dark conditions. After 24 h exposure to nanoparticles, different biological parameters such as cell viability, proliferation, infectivity, and infection index were investigated under UV/IR/dark conditions. In this study, the highest antileishmanial activity was seen for Ag NPs, followed by Au NPs, TiO₂ NPs, ZnO NPs, and MgO NPs. Both UV and IR light increased antileishmanial properties of all nanoparticles. In spite of antileishmanial activity of nanoparticles under UV, IR, and dark conditions, these nanoparticles had high cytotoxicity on macrophages, which must be considered in future studies. The authors declare that the use of nanoparticles for treatment of CL may have both positive and negative consequences.