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UK Consensus Statement on Safe Clinical Prescribing of Bexarotene for Patients with Cutaneous T-cell Lymphoma.
Abstract
Background Bexarotene is a synthetic retinoid from the subclass of retinoids called rexinoids which selectively activate retinoid X receptors. It has activity in cutaneous T-cell lymphoma (CTCL) and has been approved by the European Medicines Agency since 1999 for treatment of the skin manifestations of advanced-stage (IIB–IVB) CTCL in adult patients refractory to at least one systemic treatment. In vivo bexarotene produces primary hypothyroidism which may be managed with thyroxine replacement. It also affects lipid metabolism, typically resulting in raised triglycerides, which requires prophylactic lipid-modification therapy. Effects on neutrophils, glucose and liver function may also occur. These side-effects are dose dependent and may be controlled with corrective therapy or dose adjustments.
Objectives To produce a U.K. statement outlining a bexarotene dosing schedule and monitoring protocol to enable bexarotene prescribers to deliver bexarotene safely for optimal effect.
Methods Leaders from U.K. supraregional centres produced this consensus statement after a series of meetings and a review of the literature.
Results The statement outlines a bexarotene dosing schedule and monitoring protocol. This gives instructions on monitoring and treating thyroid, lipid, liver, blood count, creatine kinase, glucose and amylase abnormalities. The statement also includes algorithms for a bexarotene protocol and lipid management, which may be used in the clinical setting.
Conclusion Clinical prescribing of bexarotene for patients with CTCL requires careful monitoring to allow safe administration of bexarotene at the optimal dose.
... Furthermore, Escudero et al. [127] conducted preclinical studies by combining already available clinical drugs to enhance the anti-angiogenic ability and reduce side effects. They considered that bexarotene has an anti-angiogenic activity but could lead to dyslipidemia, whereas some clinical studies suggested that statins counteract this adverse effect [128]. Moreover, bexarotene is an RXRα high-affinity synthetic ligand, and statins can interact with peroxisome proliferator-activated receptors (PPARs). ...
... Moreover, bexarotene is an RXRα high-affinity synthetic ligand, and statins can interact with peroxisome proliferator-activated receptors (PPARs). PPARs and their heterodimer complexes with RXRα synergistically respond to the agonists of RXR [128]. Finally, the authors demonstrated that ro-suvastatin combined with bexarotene reduced AAA formation, inflammation, and neovascularization compared with their single treatment and the blank control [128]. ...
... PPARs and their heterodimer complexes with RXRα synergistically respond to the agonists of RXR [128]. Finally, the authors demonstrated that ro-suvastatin combined with bexarotene reduced AAA formation, inflammation, and neovascularization compared with their single treatment and the blank control [128]. Furthermore, combined therapy inhibited EC vascularization, sprouting, and the release of angiogenic factors in an in vivo Matrigel assay and ex vivo murine aortic ring assay [127]. ...
Aortic aneurysm and aortic dissection (AA/AD) are critical aortic diseases with a hidden onset and sudden rupture, usually resulting in an inevitable death. Several pro- and anti-angiogenic factors that induce new capillary formation in the existing blood vessels regulate angiogenesis. In addition, aortic disease mainly manifests as the proliferation and migration of endothelial cells of the adventitia vasa vasorum. An increasing number of studies have shown that angiogenesis is a characteristic change that may promote AA/AD occurrence, progression, and rupture. Furthermore, neocapillaries are leaky and highly susceptible to injury by cytotoxic agents, which promote extracellular matrix remodeling, facilitate inflammatory cell infiltration, and release coagulation factors and proteases within the wall. Mechanistically, inflammation, hypoxia, and angiogenic factor signaling play important roles in angiogenesis in AA/AD under the complex interaction of multiple cell types, such as smooth muscle cells, fibroblasts, macrophages, mast cells, and neutrophils. Therefore, based on current evidence, this review aims to discuss the manifestation, pathological role, and underlying mechanisms of angiogenesis involved in AA/AD, providing insights into the prevention and treatment of AA/AD.
... 4 Bexarotene is a retinoid X receptor-sensitive retinoid commonly used for the oral treatment of CTCL. 5 However, due to adverse effects of bexarotene treatment, patients on bexarotene require careful monitoring for lipid, thyroid, liver, blood count, creatine kinase, glucose, and amylase abnormalities. [6][7][8][9] Among the adverse effects of bexarotene, hypertriglyceridemia is clinically problematic. [6][7][8][9][10] Despite lifestyle management and prophylactic use of lipid-lowering agents, hypertriglyceridemia is often unavoidable in patients on bexarotene. ...
... [6][7][8][9] Among the adverse effects of bexarotene, hypertriglyceridemia is clinically problematic. [6][7][8][9][10] Despite lifestyle management and prophylactic use of lipid-lowering agents, hypertriglyceridemia is often unavoidable in patients on bexarotene. 9 In phase 1 and 2 studies involving Japanese CTCL patients, grade 3 and 4 hypertriglyceridemia often led to a bexarotene dose reduction or treatment suspension. ...
... [6][7][8][9][10] Despite lifestyle management and prophylactic use of lipid-lowering agents, hypertriglyceridemia is often unavoidable in patients on bexarotene. 9 In phase 1 and 2 studies involving Japanese CTCL patients, grade 3 and 4 hypertriglyceridemia often led to a bexarotene dose reduction or treatment suspension. 8 In phase 2 and 3 studies, pancreatitis was reported in patients with very severe hypertriglyceridemia. 6,7 Bexarotene-associated hypertriglyceridemia is a risk factor for cardiovascular disease, and thus patients with risk factors of cardiovascular disease who are treated with bexarotene should be carefully monitored to prevent severe bexarotene-associated hypertriglyceridemia. 9 Cabello et al. 11 reported that genetic polymorphisms in the genes encoding apolipoprotein A5 (APOA5) and APOC3, which are associated with triglyceride (TG) levels in the general population, are associated with severe bexarotene-associated hypertriglyceridemia. ...
Bexarotene is an effective oral drug for the treatment of cutaneous T-cell lymphoma, but careful management is required due to its various side effects. In particular, hypertriglyceridemia often requires a reduction or even suspension of bexarotene therapy. The risk factors of bexarotene-associated severe hypertriglyceridemia are not clear. Here, we conducted a post hoc analysis of the data from our previous clinical trial, which confirmed the efficacy and safety of combined bexarotene and phototherapy, to evaluate the effect of body mass index on bexarotene-associated hypertriglyceridemia. Twenty-five subjects were divided into two subgroups: normal and underweight (body mass index [BMI] <25 kg/m2 group) and overweight and obese (BMI ≥25 kg/m2 group) patients. The overall incidence of hypertriglyceridemia was 81.3% (13/16) in the BMI <25 kg/m2 group and 88.9% (8/9) in the BMI ≥25 kg/m2 group. The incidence of grade ≥3 hypertriglyceridemia (≥500 mg/dL) was 7.7% (1/13) in the BMI <25 kg/m2 group and 7/8 (87.5%) in the BMI ≥25 kg/m2 group (P < 0.001). Consequently, dose reduction in the BMI ≥25 kg/m2 group was larger than that in the BMI <25 kg/m2 group. The bexarotene-induced change in the serum triglyceride concentration was significantly increased in cutaneous T-cell lymphoma patients with a higher body mass index (ρ = 0.508, P = 0.009). The area under the curve was 0.886 (95% confidence interval 0.748-1.000, P = 0.002). With a body mass index cut-off of 24.85 kg/m2 , the sensitivity and specificity for identifying grade ≥3 hypertriglyceridemia were 0.875 and 0.882, respectively. The present findings suggest that BMI ≥25 kg/m2 is a risk factor for bexarotene-associated severe hypertriglyceridemia, therefore overweight and obese patients treated with bexarotene should receive lipid-lowering drugs prophylactically. Further studies for optimizing the initial bexarotene dose in such patients are required.
... According to the United Kingdom consensus statement on safe clinical prescribing of bexarotene, TSH suppression of bexarotene is dose-dependent (Scarisbrick et al., 2013) [7]. Thus, preventive supplementation with LT4 may be appropriate when using bexarotene. ...
... According to the United Kingdom consensus statement on safe clinical prescribing of bexarotene, TSH suppression of bexarotene is dose-dependent (Scarisbrick et al., 2013) [7]. Thus, preventive supplementation with LT4 may be appropriate when using bexarotene. ...
... It was recommended that LT4 be initiated from day one. LT4 can be started at a low dose of 25-50 µg daily and subsequently titrated to keep the fT 4 in the upper third of the reference range [7]. In our patient, the suppression of TSH was observed when increasing the LT4 dose, which was misleading to primary care providers. ...
Bexarotene is a very rare cause of central hypothyroidism (CH) and its effects have been reported to be dose-dependent; however, the available data in the literature on dose-dependent effects are variable. The standard practice of monitoring thyroid function using thyroid-stimulating hormone (TSH) to adjust levothyroxine (LT4) dose does not apply to bexarotene since it causes CH. In CH, TSH is not reliable. Hence free tetraiodothyronine (fT4) level is used to monitor and adjust the LT4 dose. We report a case of an 81-year-old Caucasian male with cutaneous T-cell lymphoma (CTCL) who was treated with bexarotene. His pre-treatment TSH was normal at 1.6 µIU/mL (reference range: 0.46-4.68 µIU/mL). Post-bexarotene, the total tetraiodothyronine (T4) level was within the reference range, but a downward trend was noted. Eventually, total triiodothyronine (T3) dropped to a low level of 0.61 ng/mL (reference range: 0.97-1.69 ng/mL), and LT4 was initiated. Bexarotene dose was increased, but LT4 was not increased by the primary physician who relied on TSH level, which was low, and hence the existing LT4 dose was maintained. The patient had persistent symptoms of hypothyroidism and, eventually, a diagnosis of CH was made. The symptoms of hypothyroidism improved after normalizing fT4, with an increase in the LT4 dose. This case represents an example of missed CH due to bexarotene, -which led to suboptimal LT4 replacement impacting the quality of life for the patient.
... Recommendations from the manufacturer are to reduce the dose, discontinue, and/or add antilipemic therapy [1]. In studies, HMG-CoA reductase inhibitors were used to manage lipids; gemfibrozil is not recommended due to its potential for drug interactions [2]. ...
... Although a lack of management recommendations was previously mentioned, a UK consensus statement in the British Journal of Dermatology contained very detailed recommendations [2]. Prior to therapy, a low-fat diet should be counseled, along with a decrease in alcohol and vitamin A intake (the latter due to retinoid activation) [2]. ...
... Although a lack of management recommendations was previously mentioned, a UK consensus statement in the British Journal of Dermatology contained very detailed recommendations [2]. Prior to therapy, a low-fat diet should be counseled, along with a decrease in alcohol and vitamin A intake (the latter due to retinoid activation) [2]. Fenofibrate should be started well ahead of therapy regardless of lipid profile due to the 2-3 months it could take to determine clinical efficacy (at least 1-2 weeks prior to initiation of therapy) [2]. ...
We present a case of a patient with cutaneous T-cell lymphoma started on bexarotene 300 mg/m2 due to progressing disease. The patient experienced good clinical response, but unfortunately, she developed rapid and profound hypertriglyceridemia. Although hypertriglyceridemia occurs in high incidence with bexarotene therapy, management recommendations are scarce. Due to the rise in triglycerides, atorvastatin 10 mg daily was initiated in combination with fenofibrate 120 mg daily. Triglycerides continued to increase, so the patient was instructed to take atorvastatin 40 mg, fenofibrate 120 mg, and to hold bexarotene for 2 weeks. After the 2-week break, bexarotene was restarted at 150 mg/m2.
... Bexarotene, a third-generation retinoid X receptorselective retinoid, is useful for both early and advanced CTCL, [10][11][12] and it is recommended by the NCCN as an effective systemic therapy for MF with higher skin disease burden (beyond stage IIA). 13 The ORR was 45% (25/56) for the treatment of refractory advanced-stage CTCL patients dosed at 300 mg/m 2 , and the median duration of response was 299 days. ...
... Although the incidence rate of SAEs was higher, their profiles were comparable to previous reports. [10][11][12]14 Since the efficacy of bexarotene and profiles of SAEs in the present study were comparable to the result of the clinical trial described above, the following IHC study appears to confirm previous reports. CD25, the IL-2Rα chain, is expressed on activated T cells and Tregs in healthy donors. ...
Bexarotene is often administered to phototherapy‐resistant early cutaneous T‐cell lymphoma (CTCL) patients as one of the first‐line therapies in real‐world practice. Since bexarotene reduces the expression of CCR4 in CTCL cells and CCL22 to decrease serum CCL22 levels, bexarotene inhibits the migration of CTCL cells, as well as other CCR4+ cells, such as cytotoxic T cells and regulatory T cells, in the lesional skin of CTCL. In this report, the efficacy of bexarotene in 28 cases of CTCL, as well as its correlations with immunohistochemical profiles of tumour‐infiltrating leucocytes (TILs), was retrospectively investigated. The overall response rate at 1 and 4 months for the total cohort was 70.8% (95% CI, 50.6%–86.3%) and 47.8% (95% CI, 29.2%–67.0%), respectively. The disease control rate for the total cohort at 4 months was 65.2% (95% CI, 44.8%–81.3%). The mean event‐free survival for all patients was 4.1 months (0.3–68.5 months). In addition, the immunoreactive cells were calculated using digital microscopy, suggesting that the ratio of CD25+ cells among TILs was significantly increased in patients who responded to bexarotene (p = 0.0209), whereas there were no significant differences in the ratios of CD8+ cells, granulysin+ cells, and Foxp3+ cells among TILs between responder and non‐responder patients. Collectively, the ratio of CD25 expression among TILs might be a predictive biomarker for the efficacy of bexarotene. Bexarotene is often administered to phototherapy‐resistant early cutaneous T‐cell lymphoma (CTCL) patients as one of the first‐line therapies in real‐world practice. In this report, the efficacy of bexarotene in 28 cases of CTCL, as well as its correlations with immunohistochemical profiles of tumour‐infiltrating leucocytes (TILs), was retrospectively investigated. Present study suggested that the ratio of CD25 expression among TILs might be a predictive biomarker for the efficacy of bexarotene.
... 50 micrograms) prior to initiating bexarotene is generally recommended. [144][145][146] In clinical practice, bexarotene is frequently initiated at a lower dose of 150 mg/m 2 and subsequently titrated to full doses after 4 weeks of therapy, depending upon patient tolerability. Most responses occur within 2-3 months of treatment initiation, but may be delayed. ...
... 147 Guidelines describing appropriate laboratory monitoring, supportive care, and safe clinical prescribing of bexarotene have been recently published. 146 Future studies clarifying the optimal use of bexarotene, either in combination or sequentially with other agents, are needed. studies. ...
Disease Overview
Cutaneous T‐cell lymphomas are a heterogenous group of T‐cell neoplasms involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS).
Diagnosis
The diagnosis of MF or SS requires the integration of clinical and histopathologic data.
Risk‐Adapted Therapy
TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a “risk‐adapted,” multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin‐directed therapies is preferred, as both disease‐specific and overall survival for these patients is favorable. In contrast, patients with advanced‐stage disease with significant nodal, visceral or the blood involvement are generally approached with systemic therapies, including biologic‐response modifiers, histone deacetylase inhibitors, or antibody‐based strategies, in an escalating fashion. In highly‐selected patients, allogeneic stem‐cell transplantation may be considered, as this may be curative in some patients.
... In one retrospective study, all patients treated with bexarotene developed hyperlipidemia and hypothyroidism, frequently within weeks of initiating treatment [165]. Consequently, use of lipid-lowering agents (e.g., fenofibrate) and lowdose levothyroxine (e.g., 50 mg) prior to initiating bexarotene is generally recommended [166][167][168]. In clinical practice, bexarotene is frequently initiated at a lower dose of 150 mg/m 2 and subsequently titrated to full doses after 4 weeks of therapy, depending upon patient tolerability. ...
... For responding patients, treatment should be continued until disease progression and, depending upon the quality of the response, adjunctive skin-directed therapies (e.g., PUVA, interferon) should be considered [169]. Guidelines describing appropriate laboratory monitoring, supportive care, and safe clinical prescribing of bexarotene have been recently published [168]. Future studies clarifying the optimal use of bexarotene, either in combination or sequentially with other agents, are needed. ...
http://deepblue.lib.umich.edu/bitstream/2027.42/108042/1/ajh23756.pdf
... Bexarotene is a third-generation retinoid X receptor (RXR)-selective retinoid that has been approved by the European Medicines Agency for use in the treatment of both early and advanced CTCL [60,61]. Since bexarotene has been used for decades in the treatment of CTCLs, several preclinical studies have suggested the anti-CTCL mechanisms of bexarotene both in vitro and in vivo [12,15,61]. ...
... Bexarotene is a third-generation retinoid X receptor (RXR)-selective retinoid that has been approved by the European Medicines Agency for use in the treatment of both early and advanced CTCL [60,61]. Since bexarotene has been used for decades in the treatment of CTCLs, several preclinical studies have suggested the anti-CTCL mechanisms of bexarotene both in vitro and in vivo [12,15,61]. Notably, multiple reports have suggested the significance of chemokine production and chemokine receptor expression in the lesional skin of CTCL [12,15]. ...
Although various anti-cutaneous T-cell lymphoma (CTCL) therapies are available for clinical use, appropriate chemotherapy lines for the treatment of CTCLs have yet to be established. Therefore, to date, various clinical trials for the treatment of advanced CTCLs are ongoing. In this review, we evaluate the therapeutic options that are available in clinical practice for treatment of early- and advanced-stage CTCLs (targeted therapies, histone deacetylase (HDAC) inhibitors, retinoids, interferons, cytotoxic drugs, etc.). We also examine clinical trials of novel regimens for the treatment of CTCLs.
... However, if TGs continually elevate, rosuvastatin, fenofibrate, omega-3 fatty acid and niacin combination is utilized to lower back to baseline. If TG levels are above 885 mg/dL, Targretin therapy should be discontinued [2]. A recent case report noted a return to baseline TGs as quick as 5 days after discontinuation of therapy [4]. ...
... A recent case report noted a return to baseline TGs as quick as 5 days after discontinuation of therapy [4]. If a patient has advanced refractory CTCL with limited treatment options, permissive elevation of TGs on Targretin should be discussed with the patient, including the risks [2]. Most notably, acute pancreatitis has been reported in patients taking Targretin with TG levels above 770 mg/dL [1]. ...
Anti-neoplastic drugs have made major advancements in oncology, however they are not without cardiovascular consequences. We present a patient with cutaneous T-cell lymphoma receiving Targretin therapy who presented with accelerated atherosclerosis. His triglyceride level (TG) was greater than 1000 mg/dL, which rapidly improved with discontinuation of Targretin.
... In one retrospective study, all patients treated with bexarotene developed hyperlipidemia and central hypothyroidism, frequently within weeks of initiating treatment.109 Consequently, use of lipid-lowering agents (eg, fenofibrate) and low-dose levothyroxine (eg, 50 micrograms) prior to initiating bexarotene is generally recommended.[110][111][112] In clinical practice, bexarotene is frequently initiated at a lower dose of 150 mg/m 2 , and subsequently titrated to full doses after 4 weeks of therapy, depending upon patient tolerability.Most responses occur within 2 to 3 months of treatment initiation, but may be delayed. ...
... For responding patients, treatment should be continued until disease progression, and depending upon the quality of the response, adjunctive skin-directed therapies (eg, PUVA, interferon) should be considered.113 Guidelines describing appropriate laboratory monitoring, supportive care, and safe clinical prescribing of bexarotene have been recently published.112 Future studies clarifying the optimal use of bexarotene, either in combination or sequentially with other agents, are needed.5.3 | HDAC inhibitorsHDACs catalyze the removal of acetyl groups from both histone and non-histone proteins. ...
Disease Overview
Cutaneous T‐cell lymphomas (CTCL) are a heterogenous group of T‐cell neoplasms involving the skin, the majority of which may be classified as Mycosis fungoides (MF) or Sézary syndrome (SS).
Diagnosis
The diagnosis of MF or SS requires the integration of clinical and histopathologic data.
Risk‐Adapted Therapy
TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a “risk‐adapted,” multi‐disciplinary approach to treatment. For patients with disease limited to the skin, skin‐directed therapies are preferred, as both disease‐specific and overall survival for these patients is favorable. In contrast, patients with advanced‐stage disease with significant nodal, visceral or blood involvement are generally approached with systemic therapies. These include biologic‐response modifiers, histone deacetylase (HDAC) inhibitors, or antibody‐based strategies, in an escalating fashion. In highly‐selected patients, allogeneic stem‐cell transplantation may be considered, as this may be curative in some patients.
... 162 Consequently, use of lipid-lowering agents (e.g., fenofibrate) and low-dose levothyroxine (e.g., 50 mg) prior to initiating bexarotene is generally recommended. [163][164][165] In clinical practice, bexarotene is frequently initiated at a lower dose of 150 mg/m 2 and subsequently titrated to full doses after 4 weeks of therapy, depending upon patient tolerability. ...
... 166 Guidelines describing appropriate laboratory monitoring, supportive care, and safe clinical prescribing of bexarotene have been recently published. 165 Future studies clarifying the optimal use of bexarotene, either in combination or sequentially with other agents, are needed. Additional HDAC inhibitors, including potent pan-HDAC inhibitors, appear to have activity in CTCL. ...
Disease overview:
Cutaneous T-cell lymphomas are a heterogenous group of T-cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS).
Diagnosis:
The diagnosis of MF or SS requires the integration of clinical and histopathologic data.
Risk-adapted therapy:
TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multi-disciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with biologic-response modifiers or histone deacetylase inhibitors prior to escalating therapy to include systemic, single-agent chemotherapy. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.
... Bexarotene, a retinoid X receptor rexinoid, have shown significant efficacy and good duration of response with low rates of disease progression in early-stage disease (107) . Bexarotene is licensed for the treatment of late-stage MF refractory to at least one systemic agent, particularly for erythrodermic disease, but monotherapy is unlikely to be effective for tumors or nodal disease (108) . ...
... The antilymphoma activity of bexarotene derives from the activation of RXR homo-and heterodimers that regulate the transcription of retinoid-regulated genes ultimately inducing cell-cycle arrest and apoptosis of cancer cells (4). However, in the clinic as well as in animal models, its administration is associated with the development of hypothyroidism that requires levothyroxine replacement therapy concomitant to initiating bexarotene treatment (7,28). Here, we described the effects of levothyroxine replacement in the antineoplastic activity of bexarotene as well as in the lymphoma immunity; and provided a rationale to improve its antilymphoma effect by combining with an inhibitor of integrin aVb3. ...
Bexarotene is a specific retinoid X receptor agonist that has been used for the treatment of cutaneous T-cell lymphoma (CTCL). Because bexarotene causes hypothyroidism, it requires the administration of levothyroxine. However, levothyroxine, in addition to its ubiquitous nuclear receptors, can activate the αVβ3 integrin that is overexpressed in CTCL, potentially interfering the antineoplastic effect of bexarotene. We thus investigated the biological effect of levothyroxine in relation to bexarotene treatment. Although in isolated CTCL cells levothyroxine decreased, in an αVβ3-dependent manner, the antineoplastic effect of bexarotene, levothyroxine supplementation in preclinical models was necessary to avoid suppression of lymphoma immunity. Accordingly, selective genetic and pharmacologic inhibition of integrin αVβ3 improved the antineoplastic effect of bexarotene plus levothyroxine replacement while maintaining lymphoma immunity. Our results provide a mechanistic rationale for clinical testing of integrin αVβ3 inhibitors as part of CTCL regimens based on bexarotene administration.
Teaser
Inhibiting αVβ3 integrin improves the antineoplastic effect of bexarotene while maintaining lymphoma immunity.
... Patients are typically initiated at 150 mg/m 2 for the first month then increased to 300 mg/m 2 . If no response is achieved after 6 months, the dose can be titrated up to a maximum of 450 mg/m 2 or patients can be transitioned to an alternate therapy [60]. Many patients do not respond to bexarotene monotherapy, and combination therapy with PUVA, extracorporeal photopheresis (ECP), methotrexate, or IFN is often needed to achieve disease remission. ...
Opinion statement
Choice of therapy in mycosis fungoides is based on both patient- and lymphoma-specific factors, such as disease characteristics, comorbidities, symptoms and effect on quality of life, potential associated toxicities of therapy, response and tolerance to prior lines of therapy, and convenience and practicality. Generally, we sequence therapies from least toxic, targeted, nonimmunosuppressive to more toxic, immunosuppressive and from single agent to multiple agents, as necessary. If more toxic, immunosuppressive agents are required to alleviate disease burden or symptoms, we generally use them just long enough to control the disease, then transition to a maintenance regimen with less toxic, less immunosuppressive agents.
... While a dose-response relationship is likely, the 300 mg/m 2 dose appears to provide the optimal risk-benefit ratio. 137 Future studies clarifying the optimal use of bexarotene, either in combination or sequentially with other agents, are needed. [146][147][148][149] angiogenesis, 150,151 aggresome formation 152 and DNA repair. ...
Disease overview
Cutaneous T‐cell lymphomas are a heterogenous group of T‐cell neoplasms involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS).
Diagnosis
The diagnosis of MF or SS requires the integration of clinical and histopathologic data.
Risk‐adapted therapy
TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a “risk‐adapted,” multi‐disciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin‐directed therapies is preferred, as both disease‐specific and overall survival for these patients is favorable. In contrast, patients with advanced‐stage disease with significant nodal, visceral or blood involvement are generally approached with systemic therapies, including biologic‐response modifiers, histone deacetylase inhibitors, or antibody‐based strategies, in an escalating fashion. In highly‐selected patients, allogeneic stem‐cell transplantation may be considered, as this may be curative in some patients.
... Actually, the oral intake of an RXR agonist including bexarotene raised the levels of APOE in the brain, decreased the accumulation of Aβ, and enhanced cognitive abilities in the amyloid mice model [76]. Furthermore, bexarotene has already been recognized as a drug by the Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma [93][94][95][96], and the emerging application of this drug for the treatment of AD has been receiving the attention of numerous researchers for many years. Clinical research recommended that bexarotene considerably reduced cognitive dysfunction in the amyloid model mouse, which expresses human APOE3 and APOE4 [77], as well as returned the APOE4-mediated neuronal and cognitive dysfunctions in mice devoid of amyloid background [75]. ...
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes chronic cognitive dysfunction. Most of the AD cases are late onset, and the apolipoprotein E (APOE) isoform is a key genetic risk factor. The APOE gene has 3 key alleles in humans including APOE2, APOE3, and APOE4. Among them, APOE4 is the most potent genetic risk factor for late-onset AD (LOAD), while APOE2 has a defensive effect. Research data suggest that APOE4 leads to the pathogenesis of AD through various processes such as accelerated beta-amyloid aggregations that raised neurofibrillary tangle formation, cerebrovascular diseases, aggravated neuroinflammation, and synaptic loss. However, the precise mode of actions regarding in what way APOE4 leads to AD pathology remains unclear. Since APOE contributes to several pathological pathways of AD, targeting APOE4 might serve as a promising strategy for the development of novel drugs to combat AD. In this review, we focus on the recent studies about APOE4-targeted therapeutic strategies that have been advanced in animal models and are being prepared for use in humans for the management of AD.
... Hypertriglyceridemia is the most common reason for discontinuing bexarotene, a drug used for treating cutaneous T-cell lymphomas 84 . Cabello et al. proposed that carriers of the APOA5 -1131T > C or APOC3 c.40 C > G mutations were the best candidates for bexarotene treatment because of their smaller triglyceride response 25 . ...
“Quantile-dependent expressivity” is a dependence of genetic effects on whether the phenotype (e.g., triglycerides) is high or low relative to its distribution in the population. Quantile-specific offspring-parent regression slopes (βOP) were estimated by quantile regression for 6227 offspring-parent pairs. Quantile-specific heritability (h2), estimated by 2βOP/(1 + rspouse), decreased 0.0047 ± 0.0007 (P = 2.9 × 10−14) for each one-percent decrement in fasting triglyceride concentrations, i.e., h2 ± SE were: 0.428 ± 0.059, 0.230 ± 0.030, 0.111 ± 0.015, 0.050 ± 0.016, and 0.033 ± 0.010 at the 90th, 75th, 50th, 25th, and 10th percentiles of the triglyceride distribution, respectively. Consistent with quantile-dependent expressivity, 11 drug studies report smaller genotype differences at lower (post-treatment) than higher (pre-treatment) triglyceride concentrations. This meant genotype-specific triglyceride changes could not move in parallel when triglycerides were decreased pharmacologically, so that subtracting pre-treatment from post-treatment triglyceride levels necessarily created a greater triglyceride decrease for the genotype with a higher pre-treatment value (purported precision-medicine genetic markers). In addition, sixty-five purported gene-environment interactions were found to be potentially attributable to triglyceride’s quantile-dependent expressivity, including gene-adiposity (APOA5, APOB, APOE, GCKR, IRS-1, LPL, MTHFR, PCSK9, PNPLA3, PPARγ2), gene-exercise (APOA1, APOA2, LPL), gene-diet (APOA5, APOE, INSIG2, LPL, MYB, NXPH1, PER2, TNFA), gene-alcohol (ALDH2, APOA5, APOC3, CETP, LPL), gene-smoking (APOC3, CYBA, LPL, USF1), gene-pregnancy (LPL), and gene-insulin resistance interactions (APOE, LPL).
... L'interaction avec l'axe thyroïdien a d'une part lieu par le biais d'une inhibition directe de la production de TSH qui survient en l'espace de quelques heures à jours après le début du traitement chez plus de 90% des patients. D'autre part, la dégradation des hormones thyroïdiennes périphériques est accélérée[3,4]. Tandis que le contrôle étroit de la fonction thyroïdienne suffit pour les immunothérapies/immunomodulateurs, l'administration prophylactique de lévothyroxine est déjà recommandée pour le bexarotène. Il convient ici de tenir compte du besoin accru en hormones thyroïdiennes entraîné par la dégradation accélérée. ...
... The increased catabolism of thyroid hormone was thought to be independent of peripheral deiodinase activity, and likely to be mediated by other pathways like glucuronidation and sulfation.94 The recommendations suggest initiation of LT4 at 25-50 µg per day when bexarotene treatment is started.[95][96][97] FT4 levels should be monitored every 1-2 weeks for first 4 weeks and adjusted to maintain FT4 within the upper third of the local laboratory normal range. ...
Cancer immunotherapy and targeted therapy, though less toxic than conventional chemotherapy, can increase the risk of thyroid dysfunction. Immune checkpoint inhibitors render the cancer cells susceptible to immune destruction, but also predispose to autoimmune disorders like primary hypothyroidism as well as central hypothyroidism secondary to hypophysitis. Tyrosine kinase inhibitors act by blocking vascular endothelial growth factor receptors and their downstream targets. Disruption of the vascular supply from the inhibition of endothelial proliferation damages not only cancer cells but also organs with high vascularity like the thyroid. Interferon-α, interleukin-2 and thalidomide analogues can cause thyroid dysfunction by immune modulation. Alemtuzumab, a monoclonal antibody directed against the cell surface glycoprotein CD52 causes Graves' disease during immune reconstitution. Metaiodobenzylguanidine, combined with 131-iodine, administered as a radiotherapeutic agent for tumours derived from neural crest cells, can cause primary hypothyroidism. Bexarotene can produce transient central hypothyroidism by altering the feedback effect of thyroid hormone on the pituitary gland. Thyroid dysfunction can be managed in the usual manner without a requirement for dose reduction or discontinuation of the implicated agent. This review aims to highlight the effect of various anticancer agents on thyroid function. Early recognition and appropriate management of thyroid disorders during cancer therapy will help to improve treatment outcomes.
... Bexarotene is a third-generation retinoid X receptor (RXR)selective retinoid that has been approved for use in the treatment of both early and advanced CTCL (7)(8)(9). Although bexarotene has been used for decades in the treatment of CTCL, and several preclinical studies have suggested anti-CTCL mechanisms are involved in the efficacy of this drug (10)(11)(12), little is known about the exact mechanisms underlying its anti-tumor effects in CTCL patients in vivo (7-9, 11, 12). ...
Bexarotene is a third-generation retinoid X receptor-selective retinoid that has been approved for use in the treatment of both early and advanced cutaneous T-cell lymphoma (CTCL). Although bexarotene has been used for decades in the treatment of CTCL, little is known about the mechanisms underlying its anti-tumor effects in CTCL patients. This study therefore focused on the immunomodulatory effects of bexarotene in vivo using an EL4 mouse T-cell lymphoma model, followed by investigation in CTCL patients treated with bexarotene. Intraperitoneal injection of bexarotene significantly decreased expressions of CCL22, CXCL5, CXCL10, and p19 in the tumor microenvironment. Based on those results, we then evaluated serum levels of CCL22, CXCL5, and CXCL10 in 25 patients with CTCL, revealing that CCL22 was significantly increased in advanced CTCL compared with early CTCL. Next, we evaluated serum levels of CCL22, CXCL5, and CXCL10 in CTCL patients treated with bexarotene. Serum levels of CCL22 were significantly decreased in 80% of CTCL patients who responded to bexarotene therapy. In addition, immunofluorescence staining revealed CD163+ M2 macrophages as the main source of CCL22. Moreover, bexarotene decreased the production of CCL22 by M2 macrophages generated from monocytes in vitro. Our findings suggest that the clinical benefits of bexarotene are partially attributable to suppressive effects on the production of CCL22 by M2-polarized tumor-associated macrophages.
... Thus, bexarotene is recommended as the second-line treatment for early-stage MF, and the first-line treatment in advanced-stage MF, following the U.K. consensus guidelines for bexarotene prescribing and management. 5 The newly developed antibody therapies for treatment of MF and SS have been appraised in addition to the use of preexisting antibodies. Antibody therapies were not recommended to be used for patients with early-stage disease. ...
Linked Article: Gilson et al. Br J Dermatol 2019; 180:496–526.
... 77 6.2.2.2 Stage IIB mycosis fungoides (MF); stage III-IVA1 erythrodermic MF/S ezary syndrome (SS); stage IVA2-B MF/SS Bexarotene is licensed in the European Union for the treatment of late-stage MF/SS refractory to at least one systemic agent, and U.K. consensus guidelines for bexarotene prescribing and management have been published. 147 Maximum responses may take 6 months, and bexarotene should be continued until loss of response. ...
... Fenretinide (N-(4-hydroxyphenyl) retinamide, 4-HPR) has been discussed as an effective Acute promyelocytic leukemia ATRA Trial Phase IV [8] B-cell lymphoma Fenretinide Trial Phase II [102] Breast carcinoma ATRA Observational study [103] Cervical carcinoma 13-cis-RA Trial Phase II [104] Cutaneous T-cell lymphoma Bexarotene Trial Phase II-III [105] Ewing's sarcoma Fenretinide Trial Phase I [106] 13-cis-RA Observational study [107] Glioblastoma multiforme 13-cis-RA Trial Phase II [108] Gliomas 13-cis-RA Trial Phase III [109] Fenretinide Trial Phase II [110] Hepatocellular carcinoma Polyprenoic acid Observational study [111] Mantle cell lymphoma Fenretinide Trial Phase II [102] Medulloblastoma Fenretinide Trial Phase I [106] 13-cis-RA Observational study [107] Multiple myeloma ATRA Trial Phase II [112] Neuroblastoma 13-cis-RA Observational study [107] Trial Phase I [9] Fenretinide Trial Phase I [106] Non-small lung cancer ATRA Trial Phase II [113] Osteosarcoma 13-cis-RA Observational study [107] Fenretinide Trial Phase I [106] Ovarian carcinoma Fenretinide Trial Phase II [114] Pancreatic carcinoma ATRA Trial Phase I [115] Papillary thyroid cancer 13-cis-RA Observational study [116] Prostate carcinoma Fenretinide Trial Phase II [117] Renal carcinoma Fenretinide Trial Phase II [118] Small cell lung cancer Fenretinide Trial Phase II [119] Squamous cell carcinoma 13-cis-RA Case series trial [120] T-cell malignancies 13-cis-RA Phase II [121] Wilm's tumor Fenretinide Phase I [106] cancer treatment, especially due to its pro-apoptotic and anti-angiogenic effects even in ATRA-resistant cell lines and with minor side-effects profile [10]. Bexarotene is a synthetic retinoid that is approved by the European Medicines Agency to treat skin manifestations of advanced-stage cutaneous T-cell lymphoma in adult patients refractory to at least one systemic treatment [11]. Several studies have suggested that bexarotene is an effective anticancer treatment that is able to decrease proliferation and promote apoptosis in cells expressing retinoid X receptors (RXRs) [12,13]. ...
Abstract For decades, retinoids and their synthetic derivatives have been well established anticancer treatments due to their ability to regulate cell growth and induce cell differentiation and apoptosis. Many studies have reported the promising role of retinoids in attaining better outcomes for adult or pediatric patients suffering from several types of cancer, especially acute myeloid leukemia and neuroblastoma. However, even this promising differentiation therapy has some limitations: retinoid toxicity and intrinsic or acquired resistance have been observed in many patients. Therefore, the identification of molecular markers that predict the therapeutic response to retinoid treatment is undoubtedly important for retinoid use in clinical practice. The purpose of this review is to summarize the current knowledge on candidate markers, including both genetic alterations and protein markers, for retinoid resistance and sensitivity in human malignancies.
... It has been shown to be better tolerated if given with concurrent lipid-lowering medications [45]. Combination with other treatments such as extracorporeal photopheresis (ECP) [45,46], interferon-alfa [45,47], methotrexate [48], denileukin diftitox [49,50], gemcitabine [51], pralatrexate [52], and psoralen with ultraviolet-A (PUVA) [45,53,54] has been reported. The most common adverse events (AEs) associated with bexarotene are hypertriglyceridemia (82%), fatigue (32%), hypercholesterolemia (30%), hypothyroidism (29%), and headache (20%) [42••, 53]. ...
Purpose of review:
Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Globally, the most common subtypes of CTCL are mycosis fungoides and Sézary syndrome. CTCL can confer significant morbidity and even mortality in advanced disease. Here we review the current and potential future treatments for advanced-stage CTCL.
Recent findings:
Heterogeneity of treatment choice has been demonstrated both in US and non-US centers. Systemic treatment choice is currently guided by prognostic features, incorporating stage, immunophenotypic and molecular findings, and patient-specific factors such as age and comorbidities. Randomized controlled studies are uncommon, and the literature is composed predominantly of retrospective, cohort, and early-phase studies. International consensus guidelines are available; however, the lack of comparative trials means that there is no clear algorithmic approach to treatment. This review article reports on the systemic treatment options in current use for advanced CTCL, and on the possible future therapies, acknowledging that an algorithmic approach is not yet forthcoming to guide treatment prioritization.
... It inhibits tumorigenesis through suppression of cell growth and stimulation of cellular differentiation [67,68]. Bexarotene is an effective oral retinoid therapy for the treatment of early and advanced-stage cutaneous T-cell lymphoma (CTCL), especially in patients who have failed on other therapies [69,70]. Interestingly, this work has highlighted the usefulness of bexarotene to inhibit NRF2 function, to produce ROS, to deplete GSH, and to modulate the expression and levels of HER1 in ovarian cancer cells. ...
NF-E2-related factor 2 (NRF2) regulates the transcription of a battery of metabolic and cytoprotective genes. NRF2 and epidermal growth factor receptors (EGFRs/HERs) are regulators of cellular proliferation and determinants of cancer initiation and progression. NRF2 and HERs confer cancers with resistance to several therapeutic agents. Nevertheless, there is limited understanding of the regulation of HER expression and activation and the link between NRF2 and HER signalling pathways. We show that NRF2 regulates both basal and inducible expression of HER1 , as treatment of ovarian cancer cells (PEO1, OVCAR3, and SKOV3) with NRF2 activator tBHQ inducing HER1 , while inhibition of NRF2 by siRNA knockdown or with retinoid represses HER1 . Furthermore, treatment of cells with tBHQ increased total and phosphorylated NRF2, HER1, and AKT levels and compromised the cytotoxic effect of lapatinib or erlotinib. Treatment with siRNA or retinoid antagonised the effect of tBHQ on NRF2 and HER1 levels and enhanced the sensitivity of ovarian cancer cells to lapatinib or erlotinib. Pharmacological or genetic inhibition of NRF2 and/or treatment with lapatinib or erlotinib elevated cellular ROS and depleted glutathione. This extends the understanding of NRF2 and its regulation of HER family receptors and opens a strategic target for improving cancer therapy.
The synthetic retinoid bexarotene (BXT), used in the treatment of cutaneous T-cell lymphoma (CTCL), has been associated with central hypothyroidism due to suppression of thyrotropin (TSH) secretion and upregulation of peripheral thyroxine (T4) and triiodothyronine (T3) metabolism. We present a case of a 41-year-old man with CTCL who developed central hypothyroidism within 1 month of receiving BXT. He required sequential uptitration of levothyroxine (LT4) over 15 months, and free T4 (FT4) and total T3 levels were normalized by a daily regimen of LT4 600 mcg and liothyronine (LT3) 15 mcg. While almost all patients regain normal hypothalamic-pituitary-thyroid axis function after cessation of BXT, there are limited data regarding LT4 and LT3 dosing required to adequately treat central hypothyroidism in patients on BXT. Our patient required an LT4 dose approximately 2.8 times the calculated weight-based dose and LT3 supplementation, demonstrating a large LT4/LT3 combination dose may be required to compensate for BXT-induced central hypothyroidism.
Endocrine disorders can exert major effects on the human skin, leading to different signs and symptoms, including skin dryness, hair loss or excessive hair growth, pruritus, pigmentary changes and hyperhidrosis. This chapter reviews these changes and provides a practical approach to patients with suspected underlying endocrinological disorders. The chapter also discusses the latest findings showing that the skin serves as a complex (neuro‐) endocrine organ by itself, and thus possesses important practical implications for future dermatological therapy.
Given that the skin is a major target organ of numerous hormones for which it expresses functional receptors, it is not surprising that excessive or insufficient systemic levels of these hormones induce clinically relevant cutaneous responses. These can manifest as general skin symptoms and signs such as pruritus, skin dryness, seborrhoea, hair loss, hypertrichosis, hirsutism, hyperhidrosis and/or hyperpigmentation, any of which prompts consideration of an underlying endocrine disease. In addition, characteristic skin lesions such as palmar erythema, gingival hyperpigmentation, stretch marks (striae distensae), acanthosis nigricans, pretibial myxoedema, necrobiosis lipoidica, melasma and acneform eruptions provide invaluable diagnostic clues to the possibility of unrecognized endocrine disease. More recently, the field has been revolutionized by the recognition that human skin is also a major endocrine and neuroendocrine organ which produces and/or metabolizes not only all classes of steroid hormones but also multiple peptide (neuro‐) hormones, neuropeptides and neurotransmitters. These impact profoundly on skin physiology and pathology at multiple levels, ranging from skin barrier function and neurogenic skin inflammation via wound healing to cutaneous stress responses. This has important implications for future dermatological therapy.
This chapter on systemic dermatological therapy aims to provide practising dermatologists with sufficient information about the most frequently used systemic medications to enable these to be used for treating skin disease to the maximum benefit and minimum detriment to their patients. The introduction covers general aspects of systemic therapy, including patient selection and education, risk reduction measures and the importance of good record keeping. Thereafter follows a detailed review of immunomodulatory and antimicrobial drugs, including antihistamines, antimalarial agents, azathioprine, ciclosporin, colchicine, dapsone, fumaric acid esters, glucocorticoids, hydroxycarbamide, methotrexate, mycophenolate mofetil, potassium iodide, protein therapies (biological drugs and intravenous immunoglobulin), retinoids, thalidomide, antibiotics, antifungal agents and antiviral drugs. The profile of each individual drug includes its pharmacological properties (formula and structure, pharmacodynamics, pharmacokinetics and, where relevant, pharmacogenetic aspects), potential adverse effects, contraindications, cautions, drug–drug interactions, pre‐treatment screening, dosage regimens, monitoring requirements and its range of licensed and off‐label dermatological usage.
Practical Clinical Oncology, 2nd edition, provides a practical and comprehensive review of the current management of common types of cancer. Introductory chapters give background information on the main treatment modalities and other key issues such as acute oncology, palliative care and clinical research, with new chapters on pathology and advanced external beam radiotherapy. Subsequent chapters describe the diagnosis and treatment of malignancies, based on tumour site or type. Finally, multiple choice questions allow the reader to test their knowledge. This edition has been fully updated to reflect the most current developments in radiotherapy, tumour biology and drug therapy. With an emphasis on practical aspects of cancer care that will be relevant to day-to-day decision making, this book is an invaluable resource on contemporary clinical management of the cancer patient for all trainees and practitioners involved in clinical oncology, medical oncology and palliative care, as well as for specialist nurses and radiographers.
Introduction:
Hypothyroidism is a common adverse event of various anticancer treatment modalities, constituting a notable paradigm of the integration of the endocrine perspective into precision oncology.
Areas covered:
The present narrative review provides a comprehensive and updated overview of anticancer treatment-induced hypothyroidism in patients with solid non-thyroid tumors. A study search was conducted on the following electronic databases: PubMed, Google Scholar, Scopus.com, ClinicalTrials.gov, and European Union Clinical Trials Register from 2011 until August 2021.
Expert opinion:
In patients with solid non-thyroid tumors, hypothyroidism is a common adverse event of radiotherapy, high dose interleukin 2 (HD IL-2), interferon alpha (IFN-α), bexarotene, immune checkpoint inhibitors (ICPi), and tyrosine kinase inhibitors (TKIs), while chemotherapy may induce hypothyroidism more often than initially considered. The path forward for the management of anticancer treatment-induced hypothyroidism in patients with solid non-thyroid tumors is an integrated approach grounded on 5 pillars: prevention, vigilance, diagnosis, treatment and monitoring. Current challenges concerning anticancer treatment-induced hypothyroidism await counteraction, namely awareness of the growing list of related anticancer treatments, identification of predictive factors, counteraction of diagnostic pitfalls, tuning of thyroid hormone replacement, and elucidation of its prognostic significance. Close collaboration of oncologists with endocrinologists will provide optimal patient care.
Emerging evidence has suggested that bexarotene, a nearly 20-year-old skin cancer drug, may be a potential drug candidate to treat Alzheimer's disease (AD) and other neurodegenerative disorders. As described in this study, a highly sensitive and rapid method, using liquid chromatography–tandem mass spectrometry (LC–MS/MS) to determine bexarotene in mouse plasma and brain tissue, was established and validated for the first time. Single-step protein precipitation utilizing methanol solution (containing 0.05 % acetic acid) as precipitation agent was employed to prepare the samples of plasma and brain tissue. Chromatographic separation in gradient elution mode was conducted via an Agilent ZORBAX SB-C18 column (50 mm×4.6 mm, 5 µm) employing methanol–ammonium acetate buffer (5 mM, pH adjusted to 4.6 with acetic acid) as mobile phase which flowed at 0.45 mL/min. The total run time was 6 min for each sample. Detection through mass spectrometric technique was operated by selected reaction monitoring (SRM) in negative electrospray ionization mode. The method was linear within the range of 10.0–15000 ng/mL for plasma and 10.0–600 ng/mL for brain tissue homogenate with the lower limit of quantification of 10.0 ng/ml. The plasma or tissue homogenate was only required 20 μL. The intra- and inter-day precision were less than 13.8 %, and the RE was between –7.4 % and 3.4 %. The method was applied to investigate the plasma pharmacokinetics and brain distribution of bexarotene in mice after intragastrically administered bexarotene with the dosage of 100 mg/kg. The results showed that both brain and plasma concentrations of bexarotene peaked at 1.0 h. Bexarotene was rapidly eliminated with a half-life of 2.0 h.
To establish real-world evidence about the safety and efficacy of bexarotene for Japanese patients with cutaneous T-cell lymphoma, we conducted a nationwide cohort study using data from post-marketing surveillance for bexarotene treatment. In total, 294 patients with cutaneous T-cell lymphoma were identified between June 2016 and June 2018. Of these, 267 patients were included as the safety analysis set. Of the 267 patients, 175 were included in the efficacy analysis set. Of these, 139 patients had mycosis fungoides, including 46 with early stage disease and 93 with advanced stage disease. Among the 139 patients with mycosis fungoides, the objective response rate was 46.8%. A significant difference in objective response rate was detected between patients who started with bexarotene at 300 mg/m² (61.6%) and patients who started with bexarotene at less than 300 mg/m² (22.6%, p < 0.001). Of the 139 patients with mycosis fungoides, 92 were treated with a combination of bexarotene plus photo(chemo)therapy. A significant difference in objective response rate was seen between bexarotene with a combination of photo(chemo)therapy (57.6%) and bexarotene without a combination of photo(chemo)therapy (25.5%, p < 0.001). Starting bexarotene at 300 mg/m² and combination with photo(chemo)therapy were detected as independent factors influencing response. Common treatment-related adverse events included hypothyroidism (85.8%), hypertriglyceridemia (68.5%), hypercholesterolemia (43.8%), and neutropenia (21.3%). Hypertriglyceridemia, hypercholesterolemia, and neutropenia occurred more frequently in patients who started with bexarotene at 300 mg/m² than patients who started with bexarotene at less than 300 mg/m² (hypertriglyceridemia, 76.4% vs. 57.0%, p = 0.001; hypercholesterolemia, 49.0% vs. 36.4%, p = 0.045; neutropenia, 28.0% vs. 12.1%, p = 0.002; respectively). The present study indicates that starting bexarotene at 300 mg/m² and combination of photo(chemo)therapy offer a promising efficacy for the treatment of patients with mycosis fungoides. Efficacy of low-dose bexarotene plus photo(chemo)therapy should be evaluated in future.
Introduction:
Cutaneous T-cell lymphoma (CTCL) is a rare non-Hodgkin's lymphoma, characterized by malignant T cells infiltrating the skin. CTCL exhibits vast heterogeneity which complicates diagnosis and therapeutic strategies. Current CTCL treatment includes skin-directed therapies (such as topical corticosteroid, topical mechlorethamine, topical bexarotene, ultraviolet phototherapy and localized radiotherapy), total skin electron beam therapy and systemic therapies. Elucidation of molecular and signaling pathways underlying CTCL pathogenesis leads to identification of innovative and personalized treatment schemes.
Areas covered:
The authors reviewed the molecular and immunological aspects of CTCL with special focus on Mycosis Fungoides (MF), Sézary Syndrome (SS) and associated systemic treatment. A literature search was conducted in PubMed and Web of Science for peer-reviewed articles published until November 2020. Novel treatment approaches including retinoids, targeted therapies, immune checkpoint and JAK/STAT inhibitors, histones deacetylase (HDAC) and mTOR inhibitors as well as proteasome inhibitors, are discussed as potential therapeutic tools for the treatment of CTCL.
Expert opinion:
Novel therapeutic agents exhibit potential beneficial effects in CTCL patients of high need for therapy such as refractory early stage cutaneous and advanced stage disease. Therapeutic schemes employing a combination of novel agents with current treatment options may prove valuable for the future management of CTCL patients.
Management of cutaneous T-cell lymphoma should provide a holistic approach to a patient's wellbeing. Treatments depend on the stage of lymphoma. Patients with the early stages tend to have a near-normal life expectancy. Management should be aimed at improving the extent of disease and reducing symptoms with minimal therapeutic adverse effects. Skin-directed treatments are preferred and may be used in combination with treatments for symptom relief such as anti-pruritic medication. In advanced stages of disease where the median life expectancy is reduced the aims are also to prevent disease progression and prolong life, and this requires a multidisciplinary approach. Symptom control remains important as patients often have painful, itchy disfiguring lesions which greatly impact on health-related quality of life.
National and international guidelines provide stage-related treatment options to be considered with first-line options followed by subsequent second-line therapies. All are listed in no particular order of preference and are chosen according to patients' needs and expertise of the treating centre. Several first-line options may be chosen before moving to the second-line options.
Three drugs received European Medicines Agency approval in 2017 and 2018 (chlormethine gel, brentuximab and mogamulizumab) but there still remains an unmet need for more improved treatments or combinations. Most treatments only result in a partial response and there is no cure for early-stage disease; as such, patients live for a long time with their disease. In the advanced stages if a good response is achieved eligible patients will be considered for an allogeneic haematopoietic stem cell transplant.
Bexarotene is useful for both early and advanced cutaneous T‐cell lymphoma (CTCL), and is sometimes applied to ultraviolet‐tolerant early CTCL patients as one of the first‐line therapies in the real world. However, continuous administration of bexarotene is sometimes difficult because of its adverse events (AE). Development of an appropriate protocol for bexarotene that can induce a consistent response for CTCL without severe AE (SAE) is needed. We retrospectively investigated 29 Japanese cases of CTCL and evaluated the efficacy of treatment and incident ratios of all AE and SAE. Objective response rate (ORR) for the overall cohort was 65.5%. ORR of the 300 mg/m² cohort (conventional dose) was 76.2%, while that of the 150–300 mg/body (low dose) with narrowband ultraviolet B light (NBUVB) cohort was 37.5%. Mean event‐free survival was 10.0 months for all patients, 6.7 months for the bexarotene conventional‐dose cohort and 19.1 months for the low‐dose with NBUVB cohort. The incident ratio of total SAE for all patients was 20.7%. The incident ratio of total SAE was 23.8% for the conventional‐dose cohort and 12.5% for the low‐dose with NBUVB cohort. Our present study suggests that low‐dose bexarotene plus NBUVB therapy is well‐tolerated and could be one of the optimal therapies for advanced CTCL.
Diagnosis and treatment of malignant (and pre-malignant) lesions is an integral part of dermatology practice. Treatments include topical, surgical, and laser-based modalities. Special cases also include radiation and chemotherapy. The involvement of oncology is recommended for late stage melanomas and all Merkel cell carcinomas.
Kutane Lymphome (cutaneous lymphomas: CL) umfassen die Gruppe der kutanen T-Zell-Lymphome (cutaneous T-cell lymphomas: CTCL), kutanen B-Zell-Lymphome (cutaneous B-cell lymphomas: CBCL) und die sog. hämatodermischen Neoplasien (HN). CL gehören zur Gruppe der Non-Hodgkin-Lymphome (NHL) und stellen in der Subgruppe der extranodalen NHL die zweithäufigste Gruppe hinter den gastrointestinalen Lymphomen dar (Jaffe et al. 2009). Man unterscheidet zwischen primären und sekundären CL. Primäre CL haben ihren Ursprung in der Haut und bleiben in der Regel darauf auch längere Zeit beschränkt, während sekundäre CL kutane Manifestationen von primär nodalen oder extranodalen Lymphomen darstellen (Willemze 2005). Die primären CL unterscheiden sich hinsichtlich klinischem Verlauf, Therapieoptionen und Prognose erheblich von nodalen und extrakutanen Lymphomen. So zeigen z. B. die primär kutanen CD30+-T-Zell-Lymphome einen gutartigen Verlauf, wogegen die nodalen Varianten als aggressiv eingestuft werden. Da die CL zumeist weniger aggressiv sind, werden sie auch weniger aggressiv behandelt.
Objective
Central hypothyroidism (CH) is a well‐known adverse effect of bexarotene treatment for cutaneous T‐cell lymphoma (CTCL). While concomitant levothyroxine therapy is recommended in these cases, associations between ethnic variation or susceptibility and bexarotene‐induced CH have not yet been reported. This study aimed to characterize the kinetics and dose‐dependency of bexarotene‐induced CH in Japanese patients.
Design and patients
Sixty‐six Japanese patients with CTCL were retrospectively investigated by evaluating thyroid function during the early phase of bexarotene therapy.
Results
At one week after bexarotene initiation, TSH and FT4 values significantly declined. However, this effect was not bexarotene dose‐dependent at least at the dose of 96‐320 mg/m². Approximately one month later, 61 patients exhibited hypothyroidism at a relatively low‐dose of bexarotene (average 251 mg/m²/day). Forty‐five study cases showed this effect at one week. Simple regression analyses indicated that higher pretreatment TSH values (at a cutoff value of 1.30: 73% sensitivity, 57% specificity) or lower normal (within the lower half of the reference range) pretreatment FT4 values (84% sensitivity, 57% specificity) were predictive of hypothyroidism at one week. The remaining 21 cases showed euthyroidism at one week, at which TSH values may roughly predict their thyroid function at one month (at a cutoff value of 0.05: 100% sensitivity, 80% specificity).
Conclusions
Preventive treatment with levothyroxine is recommended for Japanese CTCL patients prior to bexarotene therapy. Minimally, it should be considered for patients with a pretreatment TSH above 1.30, a lower normal pretreatment FT4, or a TSH below 0.05 at one week.
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Primary cutaneous CD30-positive lymphoproliferative disorders (CD30+ LPD) encompass lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (pcALCL), and borderline lesions [1]. CD30+ LPD are the second most common cutaneous T-cell lymphomas (CTCL) after mycosis fungoides (MF) and represent approximately 25% of all CTCL cases [2]. Their common phenotypic hallmark is an expression of the CD30 antigen, a cytokine receptor belonging to the tumor necrosis factor (TNF) receptor superfamily. Both LyP and pcALCL show numerous clinical, histological and immunophenotypic variants, and generally have an indolent course with a favorable prognosis. Overlapping features of LyP and pcALCL with other CD30+ T-cell lymphomas, inflammatory, and/or infectious conditions emphasize the importance of careful clinicopathologic correlation and staging.
Importance:
Hypertriglyceridemia is the most frequent and limiting adverse effect of bexarotene therapy in cutaneous T-cell lymphoma (CTCL). Despite standard prophylactic measures, there is a wide variability in the severity of this complication, which could be associated with both genetic and environmental factors.
Objectives:
To analyze the association between genetic polymorphisms of apolipoprotein genes APOA5, APOC3, and APOE and the severity of hypertriglyceridemia during bexarotene therapy and to optimize patient selection for bexarotene therapy based on adverse effect profile.
Design, setting, and participants:
This case series study was conducted in 12 university referral hospitals in Spain from September 17, 2014, to February 6, 2015. One hundred twenty-five patients with a confirmed diagnosis of CTCL who had received bexarotene therapy for at least 3 months were enrolled. Nine patients were excluded owing to missing analytic triglyceride level data, leaving a study group of 116 patients. Data on demographic and cardiovascular risk factor were collected, and a complete blood analysis, including lipid profile and genetic analysis from a saliva sample, was performed.
Main outcomes and measures:
Primary outcomes were the maximal triglyceride levels reported in association with the minor alleles of the polymorphisms studied.
Results:
Among 116 patients, the mean (SD) age was 61.2 (14.7) years, 69 (59.5%) were men, and 85 (73.2%) had mycosis fungoides, the most prevalent form of CTCL. During bexarotene therapy, 96 patients (82.7%) experienced hypertriglyceridemia, which was severe or extreme in 8 of these patients (8.3%). Patients who carried minor alleles of the polymorphisms did not show significant differences in baseline triglyceride concentrations. After bexarotene treatment, carriers of at least 1 of the 2 minor alleles of APOA5 c.-1131T>C and APOC3 c.*40C>G showed lower levels of triglycerides than noncarriers (mean [SD], 241.59 [169.91] vs 330.97 [169.03] mg/dL, respectively; P = .02).
Conclusions and relevance:
These results indicate that the screening of APOA5 and APOC3 genotypes may be useful to estimate changes in triglyceride concentrations during bexarotene treatment in patients with CTCL and also to identify the best candidates for bexarotene therapy based on the expected adverse effect profile.
Acute complications of hyperlipidemia are few. Severe hypertriglyceridemia with excess chylomicrons is one of the causes of pancreatitis. The risk of pancreatitis is exponentially associated with triglyceride level with a 200‐fold risk with concentrations above 20 mmol/L (or >2000 mg/dL; 22.4 mmol/L) though most cases occur above 34 mmol/L (3000 mg/dL). Given high variances, a cut‐off of 20 mmol/L (∼2000 mg/dL) is often used as indication for urgent referral for investigation and treatment. A particularly high‐risk group of cases is associated with the physiological triglyceride elevation of pregnancy. The real cause of pancreatitis is chylomicrons which are pro‐inflammatory, prone to coagulate, and cause damage to pancreatic cells. The genetic basis of chylomicron‐associated pancreatitis consists of both polygenic forms (multifactorial chylomicronemia syndrome, MFCS) and a rarer group of monogenic causes (familial chylomicronemia syndrome, FCS). Treatment is through a mix of dietary and pharmacological interventions and, if necessary, plasmapheresis.
Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common cutaneous T-cell lymphomas (CTCLs). Both lack curative options, and advanced-stage carries a poor prognosis. Whilst there are a number of treatments available, achieving and maintaining a durable remission remains challenging. We review current systemic treatment options as monotherapy for advanced-stage MF (IIB–IV), appraising their mechanism of action, analyzing their efficacy, and describing toxicities. Individually, reported overall response rates (ORR) vary widely in the literature and duration of responses are typically short, ranging from 7.5 to 22.4 months. Combined therapy is frequently used in an effort to boost responses, although prospective studies comparing combinations to single agent therapies are rarely conducted. While recent translational research has led to increased understanding of the immunopathogenesis of MF and SS and the development of new treatments, current standard of care therapies are not curative and have low ORR for advanced-stage disease.
In 2012, it was reported that anti-cancer drug bexarotene reduced amyloid plaque and improved mental functioning in a small sample of mice engineered to exhibit Alzheimer’s like symptoms. It has been suggested that bexarotene stimulates expression of apolipoprotein E (ApoE) leading to intracellular clearance of amyloid beta (Aβ). However the effect of bexarotene on clearance of plaques has not been seen in some mouse models. Two interesting questions that emerge are: can bexarotene destroy Aβ fibrils via direct interaction with them and how this compound impacts the lag phase in the fibril growth process. By the Thioflavin T fluorescence assay and atomic force microscopy we have shown that bexarotene prolongs the lag phase but it does not degrade Aβ fibrils. The impotence of bexarotence in destroying fibrils means that this compound is weakly bound to Aβ. On the other hand, the weak binding would prevent bexarotene from prolonging the lag phase. Thus our two main in vitro observations seem to contradict each other. In order to settle this problem at the atomic level we have performed all-atom molecular dynamics simulations in explicit water. We have demonstrated that bexarotene is not capable to reduce amyloid deposits due to weak binding to Aβ fibrils. However, it delays the self-assembly through reduction of the β-content of Aβ monomers at high enough ligand concentrations. Bexarotene is the first compound which displays such an unusual behavior. We have also shown that bexarotene has a low binding propensity to Aβ monomer and dimer.
A common dose-limiting side effect of treatment with the retinoid X receptor agonist bexarotene is dyslipidemia. We evaluated the effects of bexarotene on plasma lipid metabolism in patients with metastatic differentiated thyroid carcinoma and investigated the underlying mechanism(s) in apolipoprotein (APO) E*3-Leiden mice without (E3L) and with human cholesteryl ester transfer protein (CETP; E3L.CETP). To this end, 10 patients with metastatic differentiated thyroid carcinoma were treated with bexarotene (300 mg/d) for 6 wk. Bexarotene increased plasma triglyceride (TG; +150%), primarily associated with very low-density lipoprotein (VLDL), and raised plasma total cholesterol (+50%). However, whereas bexarotene increased VLDL-cholesterol (C) and low-density lipoprotein (LDL)-C (+63%), it decreased high-density lipoprotein (HDL)-C (-30%) and tended to decrease apoAI (-18%) concomitant with an increase in endogenous CETP activity (+44%). To evaluate the cause of the bexarotene-induced hypertriglyceridemia and the role of CETP in the bexarotene-induced shift in cholesterol distribution, E3L and E3L.CETP mice were treated with bexarotene through dietary supplementation [0.03% (wt/wt)]. Bexarotene increased VLDL-associated TG in both E3L (+47%) and E3L.CETP (+29%) mice by increasing VLDL-TG production (+68%). Bexarotene did not affect the total cholesterol levels or distribution in E3L mice but increased VLDL-C (+11%) and decreased HDL-C (-56%) as well as apoAI (-31%) in E3L.CETP mice, concomitant with increased endogenous CETP activity (+41%). This increased CETP activity by bexarotene-treatment is likely due to the increase in VLDL-TG, a CETP substrate that drives CETP activity. In conclusion, bexarotene causes combined dyslipidemia as reflected by increased TG, VLDL-C, and LDL-C and decreased HDL-C, which is the result of an increased VLDL-TG production that causes an increase of the endogenous CETP activity.
Various combination therapies are used in refractory cutaneous T-cell lymphoma (CTCL). Although bexarotene has been studied in combination with psoralen photochemotherapy (PUVA), IFN-alpha and denileukin difitox, there have been no published data assessing the efficacy of the combination of bexarotene and methotrexate.
To evaluate the efficacy and safety of an oral bexarotene and methotrexate combination for the treatment of refractory CTCL.
A retrospective study was carried out of 12 patients with refractory stage CTCL treated with an oral combination of bexarotene and methotrexate from 2000 to 2007.
Twelve patients with CTCL stage IA-IIB disease who received a combination of bexarotene and methotrexate were identified. The median dose of bexarotene was 150 mg/day (range 75-300 mg/day) and methotrexate 15 mg/week (range 5-30 mg/week). The duration of time to achieve an overall response was 6.5 months (range 3-11 months). The overall response occurred in 66% (8/12). One patient had complete response (CR = 8%) and seven had partial response (PR = 58%). Six of 12 patients progressed at some point during treatment and needed additional intervention. Tolerance to the treatment was good and commonly observed side effects were hyperlipidemia, elevated liver transaminases and a decreased white blood cell count. Limitations of the study included a restricted number of patients, relatively short evaluation times and retrospective analysis.
An oral bexarotene and methotrexate combination may be a promising future alternative to monotherapy for the treatment of CTCL, but further studies are required.
Cutaneous T-cell lymphomas (CTCL) are malignancies of T cells appearing as skin lesions and are responsive to retinoid therapy. Safety and efficacy of a novel RXR-selective retinoid (rexinoid) bexarotene (Targretin, LGD1069; Ligand Pharmaceuticals Inc, San Diego, CA) was evaluated as a single-agent oral therapy administered once daily in an open-label study in patients with refractory advanced-stage CTCL.
Ninety-four patients with biopsy-confirmed CTCL in advanced stages (IIB-IVB) were enrolled at 26 centers. Fifty-six patients received an initial dose of 300 mg/m2/d oral bexarotene and 38 started at more than 300 mg/m2/d.
Clinical complete and partial responses were reported by Primary End point Classification for the study in 45% (25 of 56) of patients enrolled at 300 mg/m2/d dosing. At more than 300 mg/m2/d, 55% (21 of 38) of patients responded, including 13% (five of 38) clinical complete. For the 300 mg/m2/d initial dose group, the rate of relapse after response was 36% and the projected median duration of response was 299 days. Improvements were also seen in overall body-surface area involvement, median index lesion surface area, adenopathy, cutaneous tumors, pruritus, and CTCL-specific quality of life. The most frequent drug-related adverse events included hypertriglyceridemia (associated rarely with pancreatitis), hypercholesterolemia, hypothyroidism, and headache.
Bexarotene is the first in a novel class of pharmacologic agents, the RXR-selective retinoids, or rexinoids. Bexarotene is orally administered, safe, and generally well tolerated with reversible side effects, and is effective for the treatment of advanced, refractory CTCL.
To determine the safety and efficacy of oral bexarotene (Targretin capsules; Ligand Pharmaceuticals Incorporated, San Diego, Calif).
The effects of 2 randomized doses of 6.5 mg/m(2) per day (with crossover for progression) vs 650 mg/m(2) per day (later modified to 300 mg/m(2) per day) were evaluated in an open-label, multicenter, phase 2 and 3 study conducted between February 1997 and November 1998.
Eighteen international cutaneous T-cell lymphoma clinics at academic referral centers.
Fifty-eight patients with biopsy-proven stage IA through IIA cutaneous T-cell lymphoma that was refractory to (or patients were intolerant of) treatment or had reached at least a 6-month response plateau under at least 2 forms of prior therapy (median of 3.5 prior therapies).
Bexarotene (Targretin capsules) administered once daily with meal for 16 weeks or longer.
Primary end point classification of overall response rate of complete and partial remissions determined by either the Physician's Global Assessment of Clinical Condition or the objective Composite Assessment of Index Lesion Severity. Body surface area, time to response, duration of disease control, time to disease progression, individual index lesion signs and symptoms, and quality of life parameters were secondary outcomes.
Responses (> or = 50% improvement) were seen in 3 (20%) of 15 patients with an initial dose at 6.5 mg/m(2) per day (95% confidence interval [CI], 0%-40%), 15 (54%) of 28 patients at 300 mg/m(2) per day (95% CI, 35%-72%), and 10 (67%) of 15 patients at above 300 mg/m(2) per day (95% CI, 43%-91%). The rate of progressive disease was 47%, 21%, and 13% at the same dose levels, respectively. Eight (73%) of 11 patients crossing over from 6.5 mg/m(2) per day to higher doses subsequently responded. The median duration of response from start of therapy could not be estimated for the 15 patients at 300 mg/m(2) per day owing to low relapse rates in 2 patients (13%); at higher doses it was 516 days. The following drug-related adverse effects were reversible and treatable: hypertriglyceridemia (46 patients [79%]), hypercholesterolemia (28 patients [48%]), headache (27 patients [47%]), central hypothyroidism (23 patients [40%]), asthenia (21 patients [36%]), and leukopenia (16 patients [28%]). No cases of drug-related neutropenic fever, sepsis, or death occurred. Pancreatitis occurred in 3 patients with triglyceride levels higher than 14.69 mmol/L (1300 mg/dL), all of whom were taking 300 mg/m(2) or more of oral bexarotene per day.
Bexarotene (Targretin capsules) (the first retinoid X receptor-selective rexinoid) was well tolerated and effective as an oral treatment for 15 (54%) of 28 patients with refractory or persistent early-stage cutaneous T-cell lymphoma at doses of 300 mg/m(2) per day. Hypertriglyceridemia and hypothyroidism require monitoring but are reversible and manageable with concomitant medication.
Bexarotene is the first synthetic rexinoid approved for the treatment of all stages of cutaneous T-cell lymphoma (CTCL) however the mechanism of bexarotene action is unknown. We examined the effects of bexarotene on induction of apoptosis and expression of its cognate receptors in well-established CTCL cell lines (MJ, Hut78, and HH).
CTCL cells were treated with 0.1, 1, and 10 microM bexarotene for 24, 48, 72, and 96 h. Apoptosis was determined by flow-cytometry analysis of sub-G(1) hypodiploid nuclei and annexin V binding populations. Apoptosis-associated proteins and retinoid receptors were detected by Western blots.
Bexarotene treatment at 1 and 10 microM for 96 h increased the number of cells with sub-G1 populations and annexin V binding in a dose-dependent manner compared with vehicle controls (DMSO) in all three cell lines, respectively. Bexarotene treatment suppressed the expression of retinoid X receptor alpha and retinoic acid receptor alpha proteins in all three lines compared with untreated controls. Bexarotene treatment decreased the protein levels of survivin, activated caspase-3, and cleaved poly(ADP-Ribose) polymerase, but had no obvious effect on expression of Fas/Fas ligand and bcl-2 proteins in all three CTCL lines.
Bexarotene treatment at clinically relevant concentrations causes apoptosis of CTCL cell lines in association with activation of caspase-3 and cleavage of poly(ADP-Ribose) polymerase, as well as down-regulation of retinoid X receptor alpha, retinoic acid receptor alpha, and survivin. These findings support apoptosis as a mechanism for bexarotene therapy in CTCL.
Bexarotene (Targretin oral capsules), the first RXR-selective retinoid "rexinoid" approved for all stages of cutaneous T-cell lymphoma (CTCL), had a response rate (RR) of 45% at the optimal dose of 300 mg/m(2) per day in 2 multicenter trials. With hypertriglyceridemia reported at 79%, bexarotene is often administered with lipid-lowering agents (LLAs). Statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase) may modulate class II major histocompatibility class expression and T-cell responses.
We attempted to optimize the clinical response to bexarotene by controlling dose-limiting hypertriglyceridemia and combining bexarotene with other active agents.
We prospectively evaluated 70 patients with CTCL at M. D. Anderson Cancer Center who were treated with oral bexarotene as monotherapy or in combination with other active agents.
Fifty-four patients receiving bexarotene monotherapy achieved an overall RR of 48%. Thirteen had stage IA-IIA disease (RR = 53%, 1 complete response [CR]); 41 had stage IIB-IVB disease (RR = 46%, 2 CRs). Forty-two (77%) of these also required one or more LLAs: atorvastatin (n = 29, RR 43%), atorvastatin plus fenofibrate (n = 10, RR 90%), or gemfibrozil (n = 3, RR 33%). Gemfibrozil was discontinued because it increased bexarotene and triglyceride levels. Patients taking 2 LLAs had a significantly higher RR of 90% during monotherapy than those taking one or no LLAs (P <.0001). Forty of 54 patients (74%) received thyroid hormone replacement to normalize thyroxine levels. Four patients receiving monotherapy have complete CRs of >3 years' duration and received maintenance dosing. Sixteen patients with advanced disease treated with bexarotene (225-750 mg/d) in combination with other CTCL therapies achieved an overall RR of 69% (11/16) with concomitant statin therapy. Bexarotene was safely combined with psoralen ultraviolet A (PUVA) plus interferon alfa (IFN-alpha) (n = 2, RR = 50%), with extracorporeal photopheresis (ECP) (n = 8, RR = 75%, 1 CR), with ECP/IFN-alpha (n = 4, RR =50%), with ECP/IFN-alpha/PUVA (n = 1, RR = 100%), and with IFN-alpha/PUVA/topical nitrogen mustard (n = 1, RR = 100%). Two patients receiving IFN-alpha had slight leukopenia, but rhabdomyolysis associated with multiple LLAs did not occur.
This single-center study supports the safety and efficacy of bexarotene as both a monotherapy and a combination therapy for CTCL. Long durable CRs may be achieved with oral monotherapy. Use of statins with bexarotene may also increase RRs by permitting higher doses to be administered without interruption, by modulating the immune response, or both. When bexarotene is combined with other active CTCL therapies, higher RRs were achieved in patients with advanced disease, without unacceptable side effects.
Primary cutaneous lymphomas are currently classified by the European Organization for Research and Treatment of Cancer (EORTC) classification or the World Health Organization (WHO) classification, but both systems have shortcomings. In particular, differences in the classification of cutaneous T-cell lymphomas other than mycosis fungoides, Sezary syndrome, and the group of primary cutaneous CD30+ lymphoproliferative disorders and the classification and terminology of different types of cutaneous B-cell lymphomas have resulted in considerable debate and confusion. During recent consensus meetings representatives of both systems reached agreement on a new classification, which is now called the WHO-EORTC classification. In this paper we describe the characteristic features of the different primary cutaneous lymphomas and other hematologic neoplasms frequently presenting in the skin, and discuss differences with the previous classification schemes. In addition, the relative frequency and survival data of 1905 patients with primary cutaneous lymphomas derived from Dutch and Austrian registries for primary cutaneous lymphomas are presented to illustrate the clinical significance of this new classification.
Fenofibrate is a fibric acid derivative indicated for use in the treatment of primary hypercholesterolaemia, mixed dyslipidaemia and hypertriglyceridaemia in adults who have not responded to nonpharmacological measures. Its lipid-modifying effects are mediated by activation of peroxisome proliferator-activated receptor-α. Fenofibrate also has nonlipid (i.e. pleiotropic) effects (e.g. it reduces fibrinogen, C-reactive protein and uric acid levels and improves flow-mediated dilatation).
Fenofibrate improves lipid levels (in particular triglyceride [TG] and high-density lipoprotein-cholesterol [HDL-C] levels) in patients with primary dyslipidaemia. Its lipid-lowering profile means that fenofibrate is particularly well suited for use in atherogenic dyslipidaemia (characterised by high TG levels, low HDL-C levels and small, dense low-density lipoprotein [LDL] particles), which is commonly seen in patients with the metabolic syndrome and type 2 diabetes mellitus. Indeed, fenofibrate improves the components of atherogenic dyslipidaemia in patients with these conditions, including a shift from small, dense LDL particles to larger, more buoyant LDL particles. Greater improvements in lipid levels are seen when fenofibrate is administered in combination with an HMG-CoA reductase inhibitor (statin) or in combination with ezetimibe, compared with monotherapy with these agents. In the DAIS study, fenofibrate significantly slowed the angiographic progression of focal coronary atherosclerosis in patients with type 2 diabetes. In terms of clinical outcomes, although no significant reduction in the risk of coronary events was seen with fenofibrate in the FIELD trial in patients with type 2 diabetes, treatment was associated with a significantly reduced risk of total cardiovascular disease (CVD) events, primarily through the prevention of non-fatal myocardial infarction and coronary revascularisation. Subgroup analyses revealed significant reductions in total CVD events and coronary heart disease events in patients with no previous CVD, suggesting a potential role for primary prevention with fenofibrate in patients with early type 2 diabetes. Improvements were also seen in microvascular outcomes with fenofibrate in the FIELD trial. Fenofibrate is generally well tolerated, both as monotherapy and when administered in combination with a statin. Combination therapy with fenofibrate plus a statin appears to be associated with a low risk of rhabdomyolysis; no cases of rhabdomyolysis were reported in patients receiving such therapy in the FIELD trial. Thus, fenofibrate is a valuable lipid-lowering agent, particularly in patients with atherogenic dyslipidaemia.
Bexarotene is the first synthetic retinoid X receptor-selective retinoid (rexinoid) approved for the treatment of cutaneous T-cell lymphoma (CTCL). However, little is known about the signalling pathways by which it exerts its anticarcinogenic effect.
To characterize the effects of bexarotene in CTCL cell lines and elucidate the underlying molecular pathways of its antineoplastic effect.
The cell lines Hut-78, HH and MJ were used. Cell viability was assessed with the XTT assay. The self-renewal potential of cells after bexarotene treatment was studied with the methylcellulose clonogenic assay. Flow cytometry was used to analyse the effects on cell cycle, Ki-67 expression and apoptosis induction. Cell cycle and apoptosis-related protein expression were determined by Western blot and immunofluorescence.
Bexarotene induced a loss of viability and more pronounced inhibition of clonogenic proliferation in HH and Hut-78 cells, whereas the MJ line exhibited resistance. Bexarotene upregulated and activated Bax in sensitive lines, although not enough to signal significant apoptosis. Instead, all data point to the inhibition of proliferation, rather than apoptosis, as the main mechanistic action of the rexinoid. Bexarotene signals both G(1) and G(2)/M arrest by the modulation of critical checkpoint proteins. We further found that bexarotene activates p53 by phosphorylation at Ser15, which influences the binding of p53 to promoters for cell cycle arrest, induces p73 upregulation, and, in concordance, also modulates some p53/p73 downstream target genes, such as p21, Bax, survivin and cdc2. Bexarotene-mediated ataxia telangiectasia mutated protein (ATM) activation in all studied lines suggests that ATM is likely to be the p53/p73 upstream activator.
Our data indicate for the first time that bexarotene exerts its effect in CTCL mainly by triggering the p53/p73-dependent cell cycle inhibition pathway, probably by upstream ATM activation. Therefore, bexarotene-modulated genes represent potential biomarkers to assess the response to treatment of patients with CTCL.
It is well established that acute pancreatitis (AP) often causes diabetes mellitus. However, whether pre-existing diabetes is associated with the development of AP remains unknown. To clarify the association of pre-existing diabetes and the development of AP, we carried out a meta-analysis of observational studies.
A computerized literature search was performed in MEDLINE (from 1 January 1966) and EMBASE (from 1 January 1974), through 31 January 2012. We also searched the reference lists of relevant articles. Summary relative risks with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. Between-study heterogeneity was assessed using Cochran's Q statistic and the I 2.
A total of seven articles (10 523 incident cases of AP) were included in this meta-analysis. Analysis of seven studies indicated that, compared with nondiabetic individuals, diabetic individuals had a 92% increased risk of development of AP (95% CI 1.50-2.47). There was significant evidence of heterogeneity among these studies (P heterogeneity<0.001, I 2=93.0%). These increased risks were independent of alcohol use, gallstones, and hyperlipidemia.
Although the current evidence supports a positive link between pre-existing diabetes and an increased risk of development of AP, additional studies, with a perfect design, are required before definitive conclusions can be drawn.
LR: 20061115; JID: 7501160; 0 (Antilipemic Agents); 0 (Cholesterol, HDL); 0 (Cholesterol, LDL); 57-88-5 (Cholesterol); CIN: JAMA. 2001 Nov 21;286(19):2401; author reply 2401-2. PMID: 11712930; CIN: JAMA. 2001 Nov 21;286(19):2400-1; author reply 2401-2. PMID: 11712929; CIN: JAMA. 2001 Nov 21;286(19):2400; author reply 2401-2. PMID: 11712928; CIN: JAMA. 2001 Nov 21;286(19):2400; author reply 2401-2. PMID: 11712927; CIN: JAMA. 2001 May 16;285(19):2508-9. PMID: 11368705; CIN: JAMA. 2003 Apr 16;289(15):1928; author reply 1929. PMID: 12697793; CIN: JAMA. 2001 Aug 1;286(5):533-5. PMID: 11476650; CIN: JAMA. 2001 Nov 21;286(19):2401-2. PMID: 11712931; ppublish
The retinoid X receptor (RXR)-agonist bexarotene and the histone deacetylase inhibitor (HDACI) vorinostat are each established monotherapies for cutaneous T-cell lymphomas (CTCLs). We investigated the combination of HDACI and retinoic acid receptor (RAR)/RXR agonists in vitro and in a phase I, multicenter, open-label, two-part dose-escalation study. The combination of bexarotene with a HDACI in vitro leads to cooperative activation of gene transcription and reduction of cell viability in human tumor cell lines. The primary clinical objective was to determine the maximum tolerated dose (MTD) of bexarotene plus vorinostat in 23 patients with CTCLs. The MTD for part I was established at vorinostat 200 mg/day plus bexarotene 300 mg/m 2 /day. The
MTD for part II was not reached. Four patients had an active response and seven patients experienced pruritus relief. We conclude that concomitant administration of vorinostat and bexarotene is feasible only if lower doses of each drug are administered relative to the product label monotherapy doses.
AMR101 is an omega-3 fatty acid agent containing ≥96% eicosapentaenoic acid ethyl ester and no docosahexaenoic acid. Previous smaller studies suggested that highly purified eicosapentaenoic acid lowered triglyceride (TG) levels without increasing low-density lipoprotein (LDL) cholesterol levels. TG-lowering therapies such as fibrates, and fish oils containing both eicosapentaenoic acid and docosahexaenoic acid, can substantially increase LDL cholesterol levels when administered to patients with very high TG levels (≥500 mg/dl). The present double-blind study randomized 229 diet-stable patients with fasting TG ≥500 mg/dl and ≤2,000 mg/dl (with or without background statin therapy) to AMR101 4 g/day, AMR101 2 g/day, or placebo. The primary end point was the placebo-corrected median percentage of change in TG from baseline to week 12. The baseline TG level was 680, 657, and 703 mg/dl for AMR101 4 g/day, AMR101 2 g/day, and placebo. AMR101 4 g/day reduced the placebo-corrected TG levels by 33.1% (n = 76, p <0.0001) and AMR101 2 g/day by 19.7% (n = 73, p = 0.0051). For a baseline TG level >750 mg/dl, AMR101 4 g/day reduced the placebo-corrected TG levels by 45.4% (n = 28, p = 0.0001) and AMR101 2 g/day by 32.9% (n = 28, p = 0.0016). AMR101 did not significantly increase the placebo-corrected median LDL cholesterol levels at 4 g/day (-2.3%) or 2 g/day (+5.2%; both p = NS). AMR101 significantly reduced non-high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein-associated phospholipase A(2), very low-density lipoprotein cholesterol, and total cholesterol. AMR101 was generally well tolerated, with a safety profile similar to that of the placebo. In conclusion, the present randomized, double-blind trial of patients with very high TG levels demonstrated that AMR101 significantly reduced the TG levels and improved other lipid parameters without significantly increasing the LDL cholesterol levels.
Bexarotene (Targretin) is a synthetic retinoid which is licensed for the treatment of advanced refractory cutaneous T-cell lymphoma (CTCL).
To summarize our experience with bexarotene for patients with CTCL with the aim of assessing efficacy and safety.
A retrospective study of 66 patients (44 male, 22 female) with mycosis fungoides (40 patients) or Sézary syndrome (26 patients) who were commenced on bexarotene prior to August 2007 was carried out. Nineteen patients had early-stage (IB-IIA) refractory mycosis fungoides and 47 patients had advanced-stage CTCL (IIB-IVB).
Fifty-two out of 66 (79%) patients completed over 1 month of therapy with an intention-to-treat response rate of 44% (29/66). Of the patients, six (9%) had a complete response, 23 (35%) had a partial response, 15 (23%) had stable disease and eight (12%) had progressive disease. Median time to maximal response was 3 months (1-9 months). Median response duration was 8 months (1 to > 48 months). Median time to progression was 9 months (3-44 months). Fourteen patients (21%) did not complete a month of bexarotene therapy. Adverse effects of the whole group included central hypothyroidism in 100% (all grade II and managed with thyroid replacement) and hyperlipidaemia in 100% (all managed with lipid-lowering therapy +/- dose reduction). Responses were seen in all stages and were higher in advanced stages: 26% (five of 19) with early-stage and 51% (24/47) of advanced-stage disease. Responses were seen in skin, blood and lymph nodes. Twenty-eight out of 66 patients were treated with bexarotene monotherapy and the remainder were on one or more additional anti-CTCL therapies.
Our data demonstrate that bexarotene is well tolerated in most patients and responses are seen in almost half of patients with all disease stages. However partial responses were not graded and would include any improvement seen in the skin, blood and lymph node.
Bexarotene is approved for the treatment of cutaneous T cell lymphomas in patients refractory to at least one prior systemic therapy. Associated hypertriglyceridaemia requires monitoring, but can readily be managed with concomitant medication, such as fenofibrate. Here we report three cases of hypertriglyceridaemia secondary to bexarotene assumption, which was adequately managed with omega-3 fatty acids. If fenofibate-related side effects occur, or a statin is required to control low-density lipoprotein-cholesterol, omega-3 fatty acids should be considered as a good alternative therapy to lower lipid levels during bexarotene treatment.
Rosuvastatin is a fully synthetic statin developed by AstraZeneca. It is a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA reductase.
We reviewed the efficacy, characteristics, safety and clinical effectiveness of rosuvastatin.
We conducted a Pubmed and Medline literature search (January 2000 to March 2008) to identify all papers on rosuvastatin published in English. Other relevant papers and textbooks from the author's personal collection were also used as references.
Rosuvastatin has a potent low-density lipoprotein cholesterol (LDL-C) lowering action. In addition it has potentially favourable effects on high-density lipoprotein (HDL), non-HDL-C, triglycerides and the apolipoprotein B : A1 ratio. Theoretically, if assumptions about these lipoprotein effects hold true and translate to better cardiovascular outcomes, rosuvastatin could prove to be the most clinically effective statin. However, while results from vascular imaging studies are encouraging overall, it is not clear whether these will translate into favourable cardiovascular outcomes because of lack of trial results. There are, as yet, no published mortality and cardiovascular outcome data from randomised, controlled trials to support LDL-C lowering with rosuvastatin rather than other statins. However, the early termination of one outcome trial has recently been announced because of clear benefits announced from rosuvastatin therapy compared with placebo.
Several staging classifications have been proposed for the cutaneous T-cell lymphomas (CTCL). However, comparisons between these schemes are difficult because differing features have been used to segregate groups. There is a critical need for a uniform staging system in CTCL. In addition to uniform classification definitions, certain minimum staging procedures should be performed in patients with CTCL. Such procedures would assist in the classification as well as in the determination of the extent of disease before and after therapy. This report will recommend procedures to be performed in all patients to provide such information.
Two series of potent retinoid X receptor (RXR)-selective compounds were designed and synthesized based upon recent observation that (E)-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1- propenyl]benzoic acid (TTNBP) binds and transactivates only the retinoic acid receptor (RAR) subtypes whereas (E)-4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8- tetrahydro-2-naphthalenyl)-1-propenyl]benzoic acid (3-methyl TTNPB) binds and transactivates both the RAR and RXR subfamilies. Addition of functional groups such as methyl, chloro, bromo, or ethyl to the 3 position of the tetrahydronaphthalene moiety of 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid (5a) and 4-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (6a) results in compounds which elicit potent and selective activation of the RXR class. Such RXR-selective compounds offer pharmacological tools for elucidating the biological role of the individual retinoid receptors with which they interact. Activation profiles in cotransfection and competitive binding assays as well as molecular modeling calculations demonstrate critical structural determinants that confer selectivity for members of the RXR subfamily. The most potent compound of these series, 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]ben zoi c acid (6b), is the first RXR-selective retinoid (designated as LGD1069) to enter clinical trials for cancer indications.
Retinoic acid receptors (RAR), thyroid hormone receptors (TR), peroxisome proliferator activated receptors (PPARs) and the orphan receptor, LXR, bind preferentially to DNA as heterodimers with a common partner, retinoid X receptor (RXR), to regulate transcription. We investigated whether RXR-selective agonists replicate the activity of ligands for several of these receptors? We demonstrate here that RXR-selective ligands (referred to as rexinoids) function as RXR heterodimer-selective agonists, activating RXR: PPARgamma and RXR:LXR dimers but not RXR:RAR or RXR:TR heterodimers. Because PPARgamma is a target for antidiabetic agents, we investigated whether RXR ligands could alter insulin and glucose signalling. In mouse models of noninsulin-dependent diabetes mellitus (NIDDM) and obesity, RXR agonists function as insulin sensitizers and can decrease hyperglycaemia, hypertriglyceridaemia and hyperinsulinaemia. This antidiabetic activity can be further enhanced by combination treatment with PPARgamma agonists, such as thiazolidinediones. These data suggest that the RXR:PPARgamma heterodimer is a single-function complex serving as a molecular target for treatment of insulin resistance. Activation of the RXR:PPARgamma dimer with rexinoids may provide a new and effective treatment for NIDDM.
The objective of this study was to evaluate the effects of daily dietary supplementation with 1.25 g or 2.5 g of docosahexaenoic (DHA), in the absence of eicosapentaenoic acid (EPA), on serum lipids and lipoproteins in persons with combined hyperlipidemia (CHL) [serum low-density lipoprotein cholesterol (LDL-C) 130 to 220 mg/dL and triglycerides 150 to 400 mg/dL].
After a 6-week dietary stabilization period, subjects entered a 4-week single-blind placebo (vegetable oil) run-in phase. Those with adequate compliance during the the run-in were randomized into one of three parallel groups (placebo, 1.25, or 2.5 g/day DHA) for 6 weeks of treatment. Supplements were administered in a triglyceride form contained in gelatin capsules. Primary outcome measurements were plasma phospholipid DHA content, serum triglycerides, high-density lipoprotein cholesterol (HDL-C). LDL-C and non-HDL-C.
The DHA content of plasma phospholipids increased dramatically (2 to 3 fold) in a dose-dependent manner. Significant (p < 0.05) changes were observed in serum triglycerides (17 to 21% reduction) and HDL-C (6% increase) which were of similar magnitude in both DHA groups. Non-HDL-C [+1.6 (NS) and +5.7% (p < 0.04)] and LDL-C [+9.3% (NS) and +13.6% (p < 0.001)] increased in the DHA treatment groups. All lipid effects reached an apparent steady state within the first 3 weeks of treatment.
Dietary DHA, in the absence of EPA, can affect lipoprotein cholesterol and triglyceride levels in patients with combined hyperlipidemia. The desirable triglyceride and HDL-C changes were present at a dose which did not significantly increased non-HDL-C or LDL-C. These preliminary findings suggest that dietary supplementation with 1.25 g DHA/day, provided in a triglyceride form, may be an effective tool to aid in the management of hypertriglyceridemia.
The occurrence of symptomatic central hypothyroidism (characterized by low serum thyrotropin and thyroxine concentrations) in a patient with cutaneous T-cell lymphoma during therapy with the retinoid X receptor-selective ligand bexarotene led us to hypothesize that such ligands could reversibly suppress thyrotropin production by a thyroid hormone-independent mechanism and thus cause central hypothyroidism.
We evaluated thyroid function in 27 patients with cutaneous T-cell lymphoma who were enrolled in trials of high-dose oral bexarotene at one institution. In addition, we evaluated the in vitro effect of triiodothyronine, 9-cis-retinoic acid, and the retinoid X receptor-selective ligand LGD346 on the activity of the thyrotropin beta-subunit gene promoter.
The mean serum thyrotropin concentration declined from 2.2 mU per liter at base line to 0.05 mU per liter during treatment with bexarotene (P<0.001), and the mean serum free thyroxine concentration declined from 1.0 ng per deciliter (12.9 pmol per liter) at base line to 0.45 ng per deciliter (5.8 pmol per liter) (P<0.001) during treatment. The degree of suppression of thyrotropin secretion tended to be greater in patients treated with higher doses of bexarotene (>300 mg per square meter of body-surface area per day) and in those with a history of treatment with interferon alfa. Nineteen patients had symptoms or signs of hypothyroidism, particularly fatigue and cold intolerance. The symptoms improved after the initiation of thyroxine therapy, and all patients became euthyroid after treatment with bexarotene was stopped. In vitro, LGD346 suppressed the activity of the thyrotropin beta-subunit gene promoter in thyrotrophs by as much as 50 percent, an effect similar to that of triiodothyronine and 9-cis-retinoic acid.
Hypothyroidism may develop in patients with cutaneous T-cell lymphoma who are treated with high-dose bexarotene, most likely because the retinoid X receptor-selective ligand suppresses thyrotropin secretion.
The state-of-the art therapy of cutaneous T cell lymphoma (CTCL) is reviewed. Commonly used treatments for early-stage (patch/plaque) mycosis fungoides (MF) include topical corticosteroids, mechlorethamine, carmustine, ultraviolet light B and PUVA. Total skin electron beam (TSEB) therapy is indicated for widespread infiltrated plaque and tumor stage disease. Low-dose methotrexate is often useful for resistant patch/plaque MF and erythrodermic CTCL. Interferon alpha (IFN-alpha) is indicated for methotrexate failures and recurrent tumors following TSEB therapy. Photopheresis may be helpful for early-stage erythrodermic CTCL but is very costly. Retinoids may be of value for early and moderately advanced CTCL particularly in combination with other agents such as IFN-alpha and PUVA. Systemic disease usually requires combination chemotherapy such as that used for non-Hodgkin's lymphoma; however, responses are usually short lived.
We report the case of a 43-year-old male patient with persistent multifocal, skin-restricted, CD30-positive, large T-cell lymphoma. Combination therapy of systemic interferon alfa and oral bexarotene was initiated on an experimental basis in the hope of circumventing therapies such as methotrexate, radiotherapy, or multiple-agent chemotherapy that may be required in such cases. This treatment was associated with rapid and marked regression of the patient's cutaneous lesions. (J Am Acad Dermatol 2001;45:914-8.)
An international group of experts advocate that clinicians address low high-density lipoprotein concentrations in lipid management of patients at high risk of coronary events. A treatment goal is recommended for high-density lipoprotein cholesterol of greater than or equal to40 mg/dl (greater than or equal to 1 mmol/L).
Rosuvastatin is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor used in the treatment of patients with dyslipidaemia. Rosuvastatin is not extensively metabolised and has a low propensity for drug interactions.
▴ In well designed trials of between 6 and 52 weeks’ duration, rosuvastatin was superior to atorvastatin, simvastatin and pravastatin in improving the lipid profile of patients with hypercholesterolaemia. In a 1-year dose-titration study, rosuvastatin 13.4mg daily (mean dose) allowed more patients to achieve US National Cholesterol Education Program (Adult Treatment panel II)[NCEP] target low-density lipoprotein (LDL)-cholesterol levels than atorvastatin 20.8mg daily (98 vs 87%) with the difference most marked in high-risk patients (97 vs 61%).
▴ Similarly, when compared with pravastatin and simvastatin 20 mg/day in a further 1-year trial, 88% of rosuvastatin recipients [9.5 and 13.8 mg/day (mean doses)] achieved NCEP target serum LDL-cholesterol levels compared with 60 and 73% of pravastatin and simvastatin recipients, respectively, with the difference more marked in high-risk patients.
▴ In further clinical trials, rosuvastatin improved the lipid profile of patients with heterozygous or homozygous familial hypercholesterolaemia, hypertriglyceridaemia or mixed dyslipidaemias.
▴ Rosuvastatin was well tolerated in clinical trials of up to 1 years’ duration.
Bexarotene is a synthetic retinoid X receptor (RXR)-selective retinoid recently approved for treatment of cutaneous T-cell lymphoma. In clinical trials, bexarotene was found to cause severe central hypothyroidism with high frequency, associated with marked reductions in serum concentrations of thyroid-stimulating hormone (TSH) and thyroxine. Further investigation demonstrated a novel mechanism causing this effect, namely reversible, RXR-mediated, thyroid hormone-independent suppression of TSH gene expression. Treatment of patients with bexarotene-induced hypothyroidism commonly requires high doses of thyroid hormone for replacement therapy, often twice the typical doses used to treat more common etiologies of hypothyroidism. These observations suggest that bexarotene probably has two fundamental effects on thyroid function: to suppress TSH production and to increase thyroid hormone metabolic clearance. Recommendations are provided for diagnosis and treatment of this syndrome.
Statins and fibrates are well-established treatments for hyperlipidaemias and the prevention of vascular events. However, fibrate + statin therapy has been restricted following early reports of rhabdomyolysis that mainly involved gemfibrozil, originally with bovastatin, and recently, with cerivastatin. Despite this limitation, several reports describing combination therapy have been published. This review considers these studies and the relevant indications and contraindications. Statin + fibrate therapy should be considered if monotherapy or adding other drugs (e.g. cholesterol absorption inhibitors, omega-3 fatty acids ornicotinic acid) did not achieve lipid targets or is impractical. Combination therapy should be hospital-based and reserved for high-risk patients with a mixed hyperlipidaemia characterised by low density lipoprotein cholesterol (LDL) >2.6 mmol/l(100 mg/dl, high density lipoprotein cholesterol (HDL) <1.0 mmol/l (40 mg/dl) and/or triglycerides> 5.6 mmol/l (500 mg/dl. These three 'goals' are individually mentioned in guidelines. Patients should have normal renal, liver and thyroid function tests and should not be receiving therapy with cyclosporine, protease inhibitors or drugs metabolised through cytochrome P450 (especially 3A4). Combination therapy is probably best conducted using drugs with short plasma half-lives; fibrates should be prescribed in the morning and statins at night to minimise peak dose interactions. Both drug classes should be progressively titated from low doses. Regular (3-monthly) monitoring of liver function and creatine kinase is required. In conclusion, fibrate + statin therapy remains an option in high-risk patents. However, long-term studies involving safety monitoring and vascular endpoints are required to demonstrate the efficacy of this regimen.
These guidelines were commissioned by the British Association of Dermatologists guidelines and therapeutics subcommittee. Members of the committee are N.H.Cox (Chairman), A.S.Highet, D.Mehta, R.H.Meyrick Thomas, A.D.Ormerod, J.K.Schofield, C.H.Smith and J.C.Sterling. Members of the U.K. Cutaneous Lymphoma Group who have contributed include C.Benton, R.Cowan, C.Deardon, B.Hancock, H.Lucraft and D.Slater.
These guidelines have been prepared for dermatologists on behalf of the British Association of Dermatologists and the U.K. Cutaneous Lymphoma Group (UKCLG) and reflect the best data available at the time the report was prepared. Caution should be exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations in this report. It may be necessary or even desirable to depart from the guidelines in special circumstances. Just as adherence to guidelines may not constitute defence against a claim of negligence, so deviation from them should not be necessarily deemed negligent.
These guidelines for the management of cutaneous T-cell lymphoma have been prepared for dermatologists on behalf of the British Association of Dermatologists and the U.K. Cutaneous Lymphoma Group. They present evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiological aspects, diagnosis and investigation.
Primary cutaneous T-cell lymphomas are non-Hodgkin's lymphomas with varied clinical presentation and prognosis. The most common subtypes of cutaneous T-cell lymphomas are the epidermotropic variants mycosis fungoides and Sézary syndrome. Treatment of mycosis fungoides has encompassed a variety of modalities including the use of retinoids with several studies evaluating their efficacy. The reported benefits and duration of response have varied in published data. The biological effect of retinoids is mediated by specific receptor families, retinoic acid receptor (RAR) and retinoic X receptor (RXR), with subsequently altered gene expression. There are no data available on cutaneous T-cell lymphomas that compare RAR and RXR retinoids. The objective of our retrospective, nonrandomized, single-center study was to compare the response, survival outcomes, and toxic effects in our phase II trial of the RAR-specific retinoid, all-trans retinoic acid, with clinical use of the RXR-specific retinoid, bexarotene, in patients with mycosis fungoides/Sézary syndrome who have relapsed. There was no statistical difference in response rates (12% vs 21%), response duration (20.5 vs 7.3 months), event-free survival time (4 vs 5 months), or median survival when corrected for length of follow-up. Both have favorable toxicity profiles that can be managed with medications. The toxicity profile caused by bexarotene seems to be more limited to laboratory values and better tolerated, although generally associated with more severe grades of toxicity. In conclusion, both retinoids have modest objective response rates and, therefore, most likely will have limited impact as monotherapeutic agents. However, the immunomodulatory effects of RAR and RXR retinoids provide a rational basis for using retinoids in combination with other biologic immune response modifiers, phototherapy, or cytotoxic chemotherapy.
Mycosis fungoides, the most common form of cutaneous T-cell lymphoma, often presents as chronic eczematous or psoriasiform patches and plaques that can be resistant to a variety of single-agent treatment modalities, necessitating combination therapy.
To evaluate the efficacy of combination therapy with bexarotene and psoralen plus ultraviolet A (PUVA) in treating patients with cutaneous T-cell lymphoma (CTCL) that recurred following monotherapy with multiple agents, including electron-beam irradiation, interferon, PUVA, and topical steroids. This was done by retrospective chart review.
Retrospective chart review analysis of eight patients with CTCL ranging from stage Ia to IIb who failed multiple single-agent treatment regimens treated with low-dose oral bexarotene and PUVA combination therapy.
We noted an initial response in all eight patients and complete remission in five of the patients treated, with pruritus being the most common adverse event.
In view of its good safety profile, combination therapy with bexarotene and PUVA may be considered for patients with treatment resistant CTCL refractory to monotherapy.
There is an increasing trend among physicians to use 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in combination with other antilipidemic agents. The complementary lipid-altering effects of statins and fibric acid derivatives (fibrates) have led to an increasing use of statin/fibrate combination therapy, particularly for patients who have mixed dyslipidemia. Clinical experience indicates that there may be an increased risk of myotoxicity associated with statin/fibrate combination therapy. However, it is not known whether there are differences in the rate of myotoxicity between the use of fenofibrate and gemfibrozil in combination with statins. To evaluate this question, data from the United States Food and Drug Administration's Adverse Event Reporting System was reviewed to determine how many adverse events were reported for patients who were being treated concomitantly with statins and fibrates. The findings suggest that the use of fenofibrate in combination with statins results in fewer reports of rhabdomyolysis per million prescriptions dispensed than does the use of gemfibrozil.
For nearly 2 decades clinicians have been treating cutaneous T-cell lymphoma (CTCL) with regimens that combine interferon alfa with retinoid compounds. In December 1999 a new retinoid, bexarotene, was approved by the US Food and Drug Administration for the treatment of CTCL. At the manufacturer's recommended dose of bexarotene (300 mg/m(2) of body surface area), it has proven to be a highly effective therapy for all stages of CTCL. Nevertheless, this dose is typically associated with adverse effects including severe hyperlipidemia. Furthermore, there appears to be no standardization of dosing among physicians who treat CTCL.
We present 3 representative patients, 2 with erythrodermic CTCL and 1 with follicular mycosis fungoides, who experienced the rapid clearing of skin disease while being treated with a combination of low-dose bexarotene and low-dose recombinant interferon alfa.
Combining low-dose bexarotene with low-dose interferon alfa was well tolerated and led to rapid improvement in our patients. We review the clinical and biologic basis for this approach.
To examine the efficacy and safety of coadministered ezetimibe (EZE) with fenofibrate (FENO) in patients with mixed hyperlipidaemia.
This was a multicentre, randomized, double-blind, placebo-controlled, parallel arm trial in patients with mixed hyperlipidaemia [LDL-cholesterol (LDL-C), 3.4-5.7 mmol/L (2.6-4.7 mmol/L for patients with type 2 diabetes); triglycerides (TG), 2.3-5.7 mmol/L] and no history of coronary heart disease (CHD), CHD-equivalent disease (except for type 2 diabetes), or CHD risk score>20%. A total of 625 patients was randomized in a 1:3:3:3 ratio to one of four daily treatments for 12 weeks: placebo; EZE 10 mg; FENO 160 mg; FENO 160 mg plus EZE 10 mg (FENO+EZE). The primary endpoint compared the LDL-C lowering efficacy of FENO+EZE vs. FENO alone. LDL-C, non-HDL-cholesterol (non-HDL-C), and apolipoprotein B were significantly (P<0.001) reduced with FENO+EZE when compared with FENO or EZE alone. TG levels were significantly decreased and HDL-C was significantly increased with FENO+EZE and FENO treatments when compared with placebo (P<0.001). Coadministration therapy reduced LDL-C by 20.4%, non-HDL-C by 30.4%, TG by 44.0%, and increased HDL-C by 19.0%. At baseline, >70% of all patients exhibited the small, dense LDL pattern B profile. A greater proportion of patients on FENO+EZE and FENO alone treatments shifted from a more atherogenic LDL size pattern to a larger, more buoyant, and less atherogenic LDL size pattern at study endpoint than those on placebo or EZE. All three active therapies were well tolerated.
Coadministration of EZE with FENO provided a complementary efficacy therapy that improves the atherogenic lipid profile of patients with mixed hyperlipidaemia.
To determine the effects of bexarotene on malignant T cells isolated from the peripheral blood of patients with the leukemic variant of cutaneous T-cell lymphoma (Sézary syndrome).
Peripheral blood mononuclear cells from 9 patients with Sézary syndrome and a high burden of circulating malignant T cells (>50% of peripheral blood mononuclear cells) and 6 healthy volunteers underwent evaluation at a university medical center, to test the effects of bexarotene on T cells.
The capacity of bexarotene to induce apoptosis and its effects on T-cell cytokine production from peripheral blood lymphocytes isolated from patients with Sézary syndrome.
Bexarotene produced dose-dependent apoptosis of peripheral blood T cells from patients with Sézary syndrome. The T cells from approximately two thirds of patients were consistently sensitive to bexarotene, whereas those from the remaining one third of patients were consistently resistant to the apoptotic effects of bexarotene. Bexarotene inhibited mitogen-induced interleukin 4 production by the peripheral blood cells of patients with Sézary syndrome, and this effect correlated with sensitivity of patients' cells to apoptosis. In contrast to the retinoic acid receptor-specific retinoid, all-trans retinoic acid, bexarotene does not induce the augmentation of interferon gamma production.
Bexarotene induces apoptosis of malignant T cells from patients with Sézary syndrome, but the cells from a proportion of patients are resistant to the apoptotic effects. Interleukin 4 production, which can play a role in the systemic immunosuppression that characterizes advancing Sézary syndrome, may be inhibited by bexarotene.
Bexarotene is a retinoid drug that is approved for the treatment of cutaneous T-cell lymphoma. We report 6 cases in which the initiation of bexarotene therapy for cutaneous T-cell lymphoma was temporally associated with the progression of internal disease despite improvement in cutaneous signs and symptoms. It is possible that bexarotene contributed to this progression. Although bexarotene therapy may alleviate symptoms and signs of cutaneous T-cell lymphoma, careful surveillance of lymph nodes and solid organs during treatment is advised.
There is no doubt that lowering serum cholesterol levels reduces the risk of major coronary events. This evidence has led treatment guidelines to set progressively lower targets for low density lipoprotein cholesterol (LDL-C). However, despite widespread use of statins, substantial numbers of patients do not achieve the LDL-C goals. Using higher doses of statins in an attempt to achieve these targets may increase the risk of serious adverse effects. Furthermore, the use of combination therapy with agents such as bile acid sequestrants, niacin and fibrates has been limited by increased potential for side effects, drug interactions and poor compliance. Ezetimibe, a selective cholesterol transport inhibitor, reduces the intestinal uptake of cholesterol without affecting absorption of triglycerides or fat-soluble vitamins. In clinical studies, ezetimibe 10 mg, in combination with statins or as monotherapy, was well tolerated and reduced LDL-C by 34-53% and 17-18%, respectively. The available evidence for ezetimibe is reviewed. The role of ezetimibe in increasing the proportion of patients attaining LDL-C treatment goals is discussed.
Several reviews and guidelines on the management of mycosis fungoides and Sézary syndrome (MF/SS) have been published; however, treatment strategies for patients with MF/SS vary from institution to institution and no European consensus has yet been established. There are few phase III trials to support treatment decisions for MF/SS and treatment is often determined by institutional experience. In order to summarise the available evidence and review 'best practices' from each national group, the European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force met in September 2004 to establish European guidelines for the treatment of MF/SS. This article reviews the treatment regimens selected for inclusion in the guidelines and summarises the clinical data for treatments appropriate for each stage of MF/SS. Guideline recommendations are presented according to the quality of supporting data, as defined by the Oxford Centre for Evidence-Based Medicine. Skin-directed therapies are the most appropriate option for early-stage MF/SS and most patients can look forward to a normal life expectancy. Patients with advanced disease should be encouraged to participate in clinical trials and maintenance of quality of life should be paramount.
This article summarizes the final conclusions of the National Lipid Association (NLA) Statin Safety Task Force, based on a review and independent research of New Drug Application (NDA) information, US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) data, cohort and clinical trial results, and analysis of administrative claims database information and the assessment of its 4 Expert Panels, which focused on issues of statin safety with regard to liver, muscle, renal, and neurologic systems. Practical guidance in the form of recommendations to health professionals who manage the coronary artery disease risk of patients with statin therapy is provided.
Cutaneous T-cell lymphomas, including mycosis fungoides and Sezary syndrome, are often responsive to treatment, but current therapies have not been shown to increase survival, and in advanced stages, durable remissions are hard to achieve. We present a patient who was initially misdiagnosed with psoriasis and, 16 years later, was diagnosed with mycosis fungoides. Denileukin diftitox was used as a tumor debulking agent to give a partial response that was further improved with a combination of systemic interferon/oral bexarotene and skin-directed psorlen plus UV-A. The purpose of this case report is to show the value of sequential combination therapy for improving overall response.
Bexarotene is an oral retinoid therapy that is effective for the treatment of early and advanced-stage cutaneous T-cell lymphoma (CTCL) in patients who have failed on other therapies. However, bexarotene treatment is associated with unavoidable side-effects, in particular hypertriglyceridaemia and hypothyroidism, which are manageable with adequate concomitant medications and are reversible on cessation of treatment. A pragmatic strategy for minimizing bexarotene-associated hypertriglyceridaemia and hypothyroidism is suggested, based on data from the studies with bexarotene in CTCL and on day-to-day experience with this agent in the clinical setting. The strategy anticipates that these common adverse events are likely to occur and recommends the early use of preventive therapy to lower triglycerides and elevate thyroid hormone levels in the blood, followed by subsequent monitoring, dose adjustment during bexarotene treatment, and titration of the daily bexarotene dose from 150 to 300 mg m(-2), which is optimal for most patients. When further information becomes available on how bexarotene interacts with lipid metabolism and thyroid function, the management approach suggested here may need to be changed.
Fenofibrate is a fibric acid derivative indicated for use in the treatment of primary hypercholesterolaemia, mixed dyslipidaemia and hypertriglyceridaemia in adults who have not responded to nonpharmacological measures. Its lipid-modifying effects are mediated by activation of peroxisome proliferator-activated receptor-alpha. Fenofibrate also has nonlipid (i.e. pleiotropic) effects (e.g. it reduces fibrinogen, C-reactive protein and uric acid levels and improves flow-mediated dilatation). Fenofibrate improves lipid levels (in particular triglyceride [TG] and high-density lipoprotein-cholesterol [HDL-C] levels) in patients with primary dyslipidaemia. Its lipid-lowering profile means that fenofibrate is particularly well suited for use in atherogenic dyslipidaemia (characterised by high TG levels, low HDL-C levels and small, dense low-density lipoprotein [LDL] particles), which is commonly seen in patients with the metabolic syndrome and type 2 diabetes mellitus. Indeed, fenofibrate improves the components of atherogenic dyslipidaemia in patients with these conditions, including a shift from small, dense LDL particles to larger, more buoyant LDL particles. Greater improvements in lipid levels are seen when fenofibrate is administered in combination with an HMG-CoA reductase inhibitor (statin) or in combination with ezetimibe, compared with monotherapy with these agents. In the DAIS study, fenofibrate significantly slowed the angiographic progression of focal coronary atherosclerosis in patients with type 2 diabetes. In terms of clinical outcomes, although no significant reduction in the risk of coronary events was seen with fenofibrate in the FIELD trial in patients with type 2 diabetes, treatment was associated with a significantly reduced risk of total cardiovascular disease (CVD) events, primarily through the prevention of non-fatal myocardial infarction and coronary revascularisation. Subgroup analyses revealed significant reductions in total CVD events and coronary heart disease events in patients with no previous CVD, suggesting a potential role for primary prevention with fenofibrate in patients with early type 2 diabetes. Improvements were also seen in microvascular outcomes with fenofibrate in the FIELD trial. Fenofibrate is generally well tolerated, both as monotherapy and when administered in combination with a statin. Combination therapy with fenofibrate plus a statin appears to be associated with a low risk of rhabdomyolysis; no cases of rhabdomyolysis were reported in patients receiving such therapy in the FIELD trial. Thus, fenofibrate is a valuable lipid-lowering agent, particularly in patients with atherogenic dyslipidaemia.
Mixed hyperlipidemia is characterized by elevated low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and TG-rich lipoprotein levels.
In a multicenter, randomized, double-blind, placebo-controlled, parallel arm trial, eligible patients were 18 to 79 years of age, with mixed hyperlipidemia (LDL-C 130-220 mg/dL, TG 150-500 mg/dL). Patients with type 2 diabetes were limited to those with LDL-C of 100 to 180 mg/dL. Patients (N = 611) were randomized in a 3:3:3:1 ratio to one of 4 treatment arms for 12 weeks: ezetimibe/simvastatin 10/20 mg (EZE/SIMVA) + fenofibrate 160 mg (FENO), EZE/SIMVA 10/20 mg, FENO 160 mg, or placebo. The primary objective was to evaluate the LDL-C-lowering efficacy of EZE/SIMVA + FENO versus FENO monotherapy.
Low-density lipoprotein cholesterol level was significantly (P < .05) reduced with EZE/SIMVA + FENO (-45.8%) compared with FENO (-15.7%) or placebo (-3.5%), but not when compared with EZE/SIMVA (-47.1%). High-density lipoprotein cholesterol and apolipoprotein A-I levels were significantly increased with EZE/SIMVA + FENO (18.7% and 11.1%, respectively) treatment compared with EZE/SIMVA (9.3% and 6.6%) or placebo (1.1% and 1.6%), but not when compared with FENO (18.2% and 10.8%). Triglyceride, non-high-density lipoprotein cholesterol, and apolipoprotein B levels were significantly reduced with EZE/SIMVA + FENO (-50.0%, -50.5%, and -44.7%, respectively) versus all other treatments. Treatment with EZE/SIMVA + FENO was generally well tolerated with a safety profile similar to the EZE/SIMVA and FENO therapies.
Coadministration of EZE/SIMVA + FENO effectively improved the overall atherogenic lipid profile of patients with mixed hyperlipidemia. Clinical trial registry number: NCT 00093899 (http://www.ClinicalTrials.gov).
Bexarotene is one of the most active single agents for the treatment of recurring or refractory cutaneous T-cell lymphoma (CTCL). Interferon alfa has also been used for many years as an effective treatment for this disease. The results in recent case reports of the combination of bexarotene and interferon alfa have been promising. Based on more extensive results reported with the combination of other retinoids with interferon alfa, the present study attempted to determine the response rate, response duration, and safety of bexarotene (Targretin capsules, Ligand Pharmaceuticals, San Diego, Calif) alone and then with the addition of interferon alfa-2b (Intron-A, Schering-Plough, Kenilworth, NJ).
Patients with biopsy-proven CTCL, TNM stages IB, IIA, IIB-IV, were treated with oral bexarotene 300 mg/m2/day for at least 8 weeks. If a complete response was not seen after 8 weeks, interferon alfa-2b 3 million units (MU) subcutaneously was added, and increased to 5 MU if tolerated, 3 times a week.
A total of 22 patients were enrolled at 5 sites, and 18 patients were assessable for response. Overall response rate for combined bexarotene and interferon alfa was 39% (95% confidence interval [CI]: 17%-64%), including 1 patient with a clinical complete response, 6 patients with partial response, 3 patients with stable disease, and 8 patients with progressive disease. Three partial responses were first noted during the bexarotene-alone phase. Adverse events were generally manageable, and only 1 patient was withdrawn from study for hypertriglyceridemia.
The addition of interferon alfa-2b did not increase the response rate that would have been expected with bexarotene alone.