Review paper
Oral retinoids and rexinoids in cutaneous T-cell lymphomas

Introduction

Cutaneous T-cell lymphomas (CTCL) are rare lymphoproliferative disorders derived from the mature T helper cells. The CTCL can present as an indolent or aggressive process involving skin, lymph nodes, blood and, secon­dary, the internal organs. The great diversity and low annual incidence rate seems to be the main reason for difficulties in establishing the best therapeutic options. The best known subtype, mycosis fungoides (MF), has been the most frequent form of primary cutaneous T-cell lymphomas representing 60% of all CTCL cases; more aggressive Sézary syndrome (SS) occurs less frequently (5%) [1-7].

Cutaneous T-cell lyfemale F – 2 : 1) [8]. The course of the disease varies widely and depends on the patient age and the presence of extracutaneous symptoms, what has been clearly classified by the World Health Organization (WHO) and European Organization for Research and Treatment of Cancer (EORTC) [9]. Most of CTCLs, because of mild course, like MF in the early stage, lymphomatoid papulosis (LyP) or cutaneous anaplastic T-cell lymphomas (C-ALCL), requires only skin-directed therapies (SDT). However, the patients with more aggressive variants, such as SS, or those refractory to SDT (e.g. syringotropic and pilotropic mycosis fungoides), require systemic therapies, including chemotherapy (Tables 1 and 2) [10].

Retinoids, their receptors and mechanism of action

Retinoids seem to have a strong position among the therapeutic options recommended by WHO and EORTC in primary cutaneous T-cell lymphomas. As biological modifiers they have been used in CTCL in every stage for over three decades [11]. As derivatives of vitamin A, they modulate cell proliferation, differentiation and immunoregulation of epithelial cells and the mononuclear skin infiltrate [12, 13]. It is believed that retinoids may also induce cellular apoptosis and DNA fragmentation in sensitive T-cell lines [14]. The first generation of vitamin A analogues were tretinoin (all-trans-retinoic acid) and isotretinoin (13-cis-retinoin), followed by the second generation of retinoids: etretinate, acitretin, and a new aromatic retinoid (arotenoid) of the third generation: bexarotene [15].

The biologic effects of retinoids are mediated by two distinct families of intracellular receptors: retinoic acid receptors (RARs) and retinoic X receptors (RXR). Three subtypes, , b, g, have been identified for both RAR and RXR proteins [16].

The receptors for retinoids belong to a larger superfamily of receptors for steroids, as well as for thyroid hormone receptors (TR) and vitamin D receptors (VDR) (Table 3,

Figure 1) what can lead to numerous side effects [17].

Retinoic acid receptors can homodimerize or heterodimerize with RXRs to affect differentiation and cell growth, while RXRs form three different types of dimers: RXR homodimer, permissive heterodimers and nonpermissive heterodimers [18]. Retinoic X receptor homodimers and RXR permissive heterodimers (e.g. PPAR, liver X re­ceptor (LXR), pregnane X receptor (PXR)) are activated upon RXR ligand binding. This class of dimer formation triggers a conformational change of the RXR, that allows binding to the RXR. Nonpermissive heterodimers (e.g. RAR, VDR, TR) cannot be activated by the RXR agonists ligand alone, but only by the ligand of the partner receptor, alone or in combination with an RXR ligand [19, 20] (Figure 2).

Retinoic X receptors are expressed in almost every tissue of the body. Retinoic X receptor  has been expressed mainly in the liver, lung, muscle, kidney and intestine and, what is the most important for dermatologists, it is consi­dered as the major subtype in the skin. Retinoic X receptor β has been expressed ubiquitously. Retinoic X receptor γ has been found in the brain and (cardiac and skeletal)

muscles [21]. The endogenous RAR ligands are all-trans retinoic acid and 9-cis retinoic acid, with similar affinity, while RXRs can bind only 9-cis retinoic acid. RXR/RAR heterodimers bind to a specific DNA sequence – retinoic acid response elements (RAREs), while the RXR homodimers binds to the retinoid X response element (RXRE) [17].

Rexinoids, cell cycle and apoptosis

Rexinoids (e.g. bexarotene) are retinoid-derived synthetic compounds that exclusively bind to the RXRs. Bexarotene does not have significant RAR binding and transactivation of RAR-response genes except at higher dose levels [22].

Activation of RXR and its heterodimer partners lead to the multitargeted approach, which suggests that bexarotene may be an active agent in treatment of malignances [23]. Bexarotene modulates cell cycle progression by activating p53, by phosphorylation at Ser15, which influences the binding of p53 to promoters for cell cycle arrest, induces p73 upregulation, and also modulates some p53/p73 downstream target genes [24]. Dragnev et al. [25] reported that bexarotene represses the expression of cyclin D1, cyclin D3, total epidermal growth factor receptor (EGFR), and phosphor-EGFR expression with dosage-dependent in non-small cell lung cancer. Furthermore, bexarotene is an inductor of apoptosis where the caspases play a crucial role. The apoptotic caspases are separated into a hierarchy of initiators (caspase-2, -8, -9 and -10) and executioners (caspase-3, -6 and -7) [26]. Once activated initiator-caspases can activate the effector-caspases, cleaving poly-(ADP-ribose)polymerase (PARP) and generate apoptosis. The cleavage of PARP is considered to be a hallmark of apoptosis for various anti tumor agents [27]. Bexarotene can cause the apoptosis of CTCL cell lines influencing the activation of caspase-3, cleavage of PARP, and down-regulation of survivin (one of the inhibitor of apoptosis protein family (IAP) suppressing the caspase activity and protecting cells from apoptosis) [28, 29].

Bexarotene also inhibits metastasis. Yen et al. had shown that bexarotene decreases migration and invasiveness of tumor cells in a dose-dependent manner [28]. In A549 cells, treatment with bexarotene resulted in reduction in matrix metalloproteinases (MMPs), VEGF, EGF and increase in secretion of tissue inhibitors of matrix metalloproteinases (TIMPs).

Moreover, bexarotene inhibited angiogenesis. The analysis of tumor-conditioned medium indicated that bexarotene decreased the secretion of angiogenic factors and matrix metalloproteinases. The inhibitory effect of bexarotene on angiogenesis and metastases was revealed through activation of its heterodimerization partner PPARg [30].

Rexinoids present an immunomodulatory effect. They have been shown to increase interleukin-2 receptor (IL-2R) expression. Sidell et al. [31] had noticed that ATRA, a RAR-specific ligand, could upregulate the expression of IL2R on human thymocytes by increasing steady-state mRNA levels. Gorgun and Foss [32] had confirmed these findings investigating the effects of ATRA, bexarotene and alitretinoin (which binds both RAR and RXR) on human T-cell and

B-cell leukemia cell lines. All three agents evoked upregulation of both  and β components of the IL-2R. Similar findings were observed in the same study with Sézary cells and B-cell lymphocytic leukemia cells.

As mentioned before, the RXRs form heterodimers with various other nuclear hormone receptors, which in turn

act as ligand-inducing transcription regulatory factors [33, 34]. It may also work through the down-regulation of

Th2 cytokines and E- selectin on endothelial cells [35, 36]. Bexarotene inhibits malignant cells trafficking to the skin through an ability to suppress CCR4 expression among malignant lymphocytes [37].

Retinoids in cutaneous T-cell lymphomas

Isotretinoin



Isotretinoin (13-cis-retinoic acid) was the first retinoid used in MF/SS. It has been effective as monotherapy in both tumor- and plaque-stage MF at doses of 1 to 3 mg/kg/day. Kessler et al. [38] had treated 25 patients with MF including 7 patients with erythroderma and 5 patients with more than 5% of Sézary cells (SC) but not diagnosed as SS, with isotretinoin 1-2 mg/kg/day. Only 3 of 25 had complete response (CR) (stage unspecified) and median response duration was greater than 8 months (1-25 months). Molin et al. [39] had used isotretinoin in 39 patients with MF/SS. Objective response to 0.2 mg/kg/day to 2 mg/kg/day was 59% including one of 5 patients with SS [39, 40]. The potential benefit of isotretinoin was reported by Leverkus et al. [41] in a more aggressive type of MF (follicular MF), especially for the treatment of residual cysts and comedones.



Etretinate and acitretin



Etretinate was primarily FDA approved for the treatment of psoriasis and was also used in several clinical trials in MF and SS before bexarotene. It has been used successfully as monotherapy. Claudy et al. [42] had treated 6 pa­tients (5 patients with advanced MF and 1 patient with SS) with etretinate 0.8-1 mg/kg/day. Clinical response was observed in 5 of them, however without histological clearance in the skin. Etretinate was withdrawn from the market in 1998 because of its long half-life, protracted tissue storage time and prolonged risk of teratogenicity in women. It was replaced by acitretin (metabolite of etretinate) characterized by shorter half-life (49 h). Molin et al. [39] had reported clinical response in 3 of 4 patients with MF treated with acitretin but not in a patient with SS. There were no significant differences in the overall response rate (ORR) (66% vs. 59%, respectively) between patients in all stages of MF/SS treated with etretinate and acitretin.

The authors of this review have also some experience with acitretin in CTCL. 7 patients with MF (IB – III) and

2 patients with SS have been treated with acitretin in monotherapy, but the results were unsatisfactory. The combined therapy (acitretin plus PUVA) had seemed to be more effective (7 patients with advanced MF) [43].

Rexinoid in cutaneous T-cell lymphomas

Bexarotene



Bexarotene is a synthetic rexinoid that binds selectively to the retinoid X receptor (RXR) isoforms (RXR, β and g). Bexarotene was approved by FDA in 1999 and licensed in 2002 as 75 mg soft gelatin capsules for the treatment of the refractory advanced stage CTCL. However, it has also been shown to be an effective and safe therapeutic method in the early stage CTCL. It is eliminated through the hepatobiliary system and it appears to be metabolized to oxidative forms by the cytochrome p450 3A4 isozyme [44].

The recommended initial dose of bexarotene capsules is 300 mg/m²/day. That dose may be adjusted to 200 mg/ m²/day then to 100 mg/m²/day, or temporarily suspended, if necessitated by toxicity. When toxicity is controlled, doses may be carefully readjusted upward. If there is no tumor response after 8 weeks of treatment and if the initial dose of 300 mg/m²/day is well tolerated, the dose may be escalated to 400 mg/m²/day with careful monitoring. The topical form (gel) is also in the market but it is of a relatively little use. Bexarotene has been used both as monotherapy and combination therapy for CTCL stage IIB or higher MF [45, 46].

The results of the oral treatment were better in pa­tients who started with a bexarotene dose of more than 300 mg/m²/day (CR – 13%) compared with 300 mg/m²/day (CR – 2%) [47]. Bexarotene was administered for up to

97 weeks in clinical trials in CTCL, but it is well known that it should be continued as long as the patient is deriving benefit. Abbott et al. [48] had presented their experience with bexarotene in a retrospective study of 66 patients with MF (40) and SS (26 patients). Forty-seven of them had suffered from the advanced stage of CTCL (IIB-IVB) and 19 pa­tients from the early stage MF but refractory to skin-directed therapies. Bexarotene was used as a single method or combined treatment. Twenty-eight patients were started on bexarotene alone. Finally, twenty patients completed at least 1 month of monotherapy. The median starting dose was 150-300 mg/m²/day. Eight of 20 patients had tolerated 300 mg/m²/day. Among all patients who competed therapy: 2 patients (10%) had CR, 10 (50%) – OR, 6 (30%) had stable disease and progression of the diseases was observed in 2 patients (10%). Among patients with SS (9), OR was observed in 78% (7) and CR in 22% (2) of them. In a group of patients who completed the bexarotene monotherapy, the median time to progression was 11 months (3-44 months).

Promising results were also obtained by Bagot [49]. The CR was observed in 1 patient with SS who was treated with bexarotene at an initial dose of 300 mg/m²/day and the duration of response was 17 months. But there are also described several patients who did not respond to bexa­rotene in monotherapy [50, 51]. That is why bexarotene has been also used as combination regimens. Bouwhuis et al. [50] had used bexarotene with ECP in 3 patients with SS, who did not respond to the treatment [50]. But Tsirigotis et al. [52] achieved objective response in 2 patients with SS (2/2) treated in the same way (OR 100%) [52]. Also Ranki [53] had presented one patient with SS, who was treated with bexarotene and INF- with quite good response (5 months of PR).

There were few patients with SS who underwent complex therapy with bexarotene, INF-g/INF- and PUVA/TSEB, ECP and denileukin diftitox, what had revealed that bexarotene positively regulated both p55 and p75 subunits of IL2R and enhanced the susceptibility of tumor cells to denileukin diftitox. The results were much better than those achieved with rexinoids as a single agent, what has to be considered by clinicians. Response duration was over

5 months and reached even 3 years in one patient. What can be interesting, these observations confirm the efficacy of PUVA in MF/SS also in systemic disease [54-56]. Unfortunately, there have been also several reports, mainly in SS, of rapid worsening of disease after implementation of bexarotene. The mechanism of that reaction has been still unknown [50, 57-60].



Alitretinoin



Alitretinoin (9-cis-retinoic acid) binds both known nuclear retinoid receptor families – RAR and RXR [61]. Compared with other vitamin A derivatives such as bexarotene or acitretin, oral alitretinoin can have a more favorable safety profile regarding mucocutaneous side-effects and laboratory changes of thyroid parameters [62].

Molin and Ruzicka [63] had reported very good response after alitretinoin in a patient with SS. The dose of 30 mg/day was used as part of a combination regimen with ECP with very good skin response, normalization of leukocyte count (stable 5 months of follow-up) and reduction of lympha­denopathy in ultrasound [63].

All known studies and clinical trials concerning re­ti­noids and rexinoids in CTCL treatment are summarized in Tables 4 and 5.

Side effects of retinoids and rexinoids

Unfortunately, there are observed different side effects during the bexarotene treatment. The most common side effects reported in the literature are hyperlipidaemia and secondary hypothyroidism [65, 66].

Hyperlipidaemia is observed in patients taking at least 300 mg/m²/day of bexarotene. The main side effect associated to the treatment with rexinoids is the increase in triglyceride levels. This elevation is due to transactivation by LXR/RXR heterodimers of SREBP-1c (Sterol Regulatory element-binding proteins), a master transcriptional regulator of genes involved in cholesterol biosynthesis [67, 68]. In human hepatoma cells, rexinoids stimulate triglyceride synthesis by increasing ap^oC-III expression [69]. Side effects depend also on the modulation of the heterodimers with the PPARs and LXRs [70, 71].

PPAR (NR1C1) stimulates lipid metabolism downregulating or upregulating genes involved in fatty acid uptake and degradation, and also in reverse cholesterol transport. PPARg (NR1C3) acts as a regulator of adipocyte differentiation. Together, the  and β subtypes regulate the balance between catabolism and storage of long-chain fatty acids [70].

Liver X receptor (LXR) regulates cholesterol homeostasis and determines atherosclerosis susceptibility [72]. Liver X receptor  (NR1H2) is responsible for the cholesterol metabolism in the liver, whereas LXRb (NR1H3) activates reverse cholesterol transport from the peripheral tissues to the liver by increasing the levels of plasma HDLs [71]. A cross-talk of LXR and PPAR is established in the homeostasis of fatty acids, since LXR regulates their synthesis and PPAR controls their degradation [67].

Activation of LXR by synthetic LXR ligands results in increased hepatic lipogenesis and plasma triglyceride levels and also in increased glucose utilization and reduced glucose output by the liver, because of the induction of hepatic glucokinase and reduced expression of some hepatic gluconeogenesis genes [67]. Interestingly, permissive RXR heterodimer partners are receptors for dietary lipids that bind with low affinity, whereas nonpermissive partners correspond to high-affinity hormone receptors [21]. In conclusion, the influence of rexinoids on the metabolism of lipids, fatty acids and glucose is complex. Different heterodimers might be modulated by the same ligand to produce effects that act in opposition [67].

Hypothyroidism had occurred in 40% of patients during the clinical trials but has been observed in nearly all patients in clinical practice. Side effects require early introducing of preventative therapy and subsequent monitoring [49, 73]. Patients treated with bexarotene often present central hypothyroidism, caused by suppression of pituitary production of thyroid-stimulating hormone (TSH) and subsequent reduction in circulating thyroid hormones [74]. Animal studies have shown that pharmacologic amounts of retinoids might decrease serum levels of TSH [75]. In vitro experiments have shown that 9-cis-retinoic acid inhibits partially TSHb promoter activity probably through the thyrotrope-restricted RXRg isoform [74].

Those and other possible side effects of bexarotene are presented in Table 6.

Conclusions

The primary cutaneous lymphomas have revealed a great diversity of clinical pictures with an indolent to rapid and aggressive course. The aggravating symptoms, such as pruritus and disfiguring skin lesions, severely affect the quality of life. Dysfunction of the immunological system in late stages, resulting in infections and secondary malignancies, had been quite often intensified by too early and too “strong” therapeutic interventions with polychemotherapy a few decades ago. Consequently, most of patients died from infectious problems secondary to immunosuppressive treatment, rather than from the lymphoma itself. The clinicians must always consider that a large group of patients with primary cutaneous lymphomas are elderly and suffer from co-morbidities, such as hypertension, diabetes etc. These factors negatively influence the side effects of treatment. Because there is no curative treatment of cutaneous lymphomas, especially mycosis fungoides and Sézary syndrome, the goal should be to achieve long-lasting remission with medicaments or procedures, which are safe and have low toxicity. For this reason, skin-directed therapy as topical corticosteroids and phototherapy as well as retinoids and rexinoids, histone deacetylase inhibitors or denileukin diftitox should always be the primary therapeutic option implemented prior to chemotherapy. Rexinoids and retinoids are the best choice in almost every stage of the disease – as monotherapy or part of combination regimens. There are no high-quality randomized clinical trials evaluating the treatment of primary cutaneous lymphomas but it seems that a higher response rate can be achieved when bexarotene is combined with other systemic treatments for CTCL. The benefits are likely to depend on the type of concomitant CTCL therapy, but no study has been adequately designed to determine the optimal combination treatment so far. Hypertriglyceridaemia and hypothyroidism are the most frequent adverse events observed during treatment, mostly limited to the laboratory abnormalities, but, anyway, leading to treatment discontinuation in a quarter of patients.

In conclusion, there are no high-quality randomized clinical trials evaluating the treatment of primary cutaneous lymphomas but the results obtained in most of studies demonstrated that oral retinoids, especially rexinoids were well tolerated and effective, achieving positive responses in nearly half the patients with CTCL, whether or not previous therapies had failed. The efficacy of bexarotene is positively correlated to the initial dose and the treatment duration and it is higher when bexarotene is combined with other systemic treatments.

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