Bexarotene In Cutaneous T-cell Lymphoma Research Articles

Inhibition of Integrin αVβ3 Signaling Improves the Antineoplastic Effect of Bexarotene in Cutaneous T-Cell Lymphoma

Inhibiting αVβ3 integrin improves the antineoplastic effect of bexarotene while maintaining lymphoma immunity.

Inhibition of the Integrin αVβ3 Improves the Immune and Anti-Lymphoma Effects of Bexarotene in Cutaneous T-Cell Lymphoma (CTCL)

Bexarotene (Bex) is an oral RXR agonist that is effective for the treatment of early and advanced-stage CTCL. However, Bex is associated with the unavoidable side effect of hypothyroidism in about 95% of pts, which is prophylactically managed with the administration of thyroid hormone (TH). Paradoxically, we found that physiological levels of TH increase the proliferation of CTCL by activating both the nuclear TRA receptor and the membrane integrin αVβ3 in these cells. Here, we determined the influence of TH replacement therapy on the anti-lymphoma activity of Bex, an unknown topic with clinical implications.Results: In standard culture conditions, Bex decreases the proliferation and viability of CTCL cell lines HuT78 and MJ. We conducted RNA-sequencing in HuT78 cells treated with Bex (vs. vehicle) to understand the mechanism/s underpinning these effects. We found that Bex regulates pathways related to “cell proliferation and differentiation” (e.g. REL, SCD, CCND1) and “immune system” (e.g. TBX21, IFNG, MX1) , which we independently validated. This suggests that Bex treatment could also impact anti-neoplastic immunity by increasing INF-gamma release from CTCL cells. We then conducted the same experiment culturing HuT78 and MJ in TH-depleted culture conditions and observed a higher effect of Bex in decreasing proliferation and viability; supporting the notion that Bex should not be administered with TH replacement. However, hypothyroidism is associated with marked immunosuppression that could favour CTCL progression and potentially affect the immune modulator effect of Bex that we described above.We thus determined the impact of TH replacement on the anti-lymphoma effect of Bex using a murine CTCL model. We implanted murine EL4 TCL cells in the hypodermis of immunocompetent C57BL/6 mice. Once tumors developed, mice were randomized into treatment with vehicle (Veh), Bex with no TH replacement (Bex) and Bex with TH replacement (BexT4+). TH replacement was done with oral administration of T4. We measured T4 in these mice plasma by RIA to assure that mice with T4 replacement reach physiological levels and those with no T4 develop hypothyroidism. Compared to Veh mice, the administration of Bex significantly decreased lymphoma growth in both conditions although slightly better in mice without T4 replacement (p<0.001 and p<0.01) for Bex and BexT4+, respectively). However, mice with Bex alone that developed hypothyroidism showed a significant decrease of CD8+CD44+ T-cells (p<0.05 vs. BexT4+) and increase of myeloid-derived suppressor cells in the tumor microenvironment and draining lymph nodes. Since infiltration of CD8+ cells decreases with CTCL progression, our data indicates that Bex treatment should be administered with T4 replacement to avoid a negative immune microenvironment.Considering the cellular effects of TH are exerted through TRA and integrin αVβ3 that can be independently modulated pharmacologically, we investigated whether integrin αVβ3 inhibition would be sufficient to blunt the TH-induced decrease on the antineoplastic efficacy of Bex. The lack of expression of integrin αVβ3 in normal T-cells offers a rationale for a selective effect on CTCL cells while sparing immune cells. In HuT78 and MJ cell lines, either αVβ3 silencing by siRNAs or pharmacologic inhibition with the clinical drug cilengitide avoided the decrease in the anti-CTCL effect of Bex upon TH supplementation. Moreover, gene expression analysis (RNA-seq and PCR) demonstrated that αVβ3 silencing induced higher (vs. Bex) up-regulation of “immune ” genes like TBX21 and INFG, or down-regulation of “proliferation” genes like REL and CCND1 .We thus tested if this mechanism can be therapeutically capitalized to improve Bex treatment in our CTCL murine model. We implanted 24 C57BL/6 mice with murine EL4 TCL cells and randomized them to vehicle (Veh), Bex with TH replacement in combination with cilengitide 40mg/kg (BexT4+Cil) or without cilengitide (BexT4+). At end of treatment, BexT4+Cil mice showed significantly smaller tumors compared with Veh and BexT4+ mice (p<0.001 and p<0.05, respectively). Importantly, the anti-tumoral immune response of CD8+CD44+ T-cells in the CTCL microenvironment and draining lymph nodes remained similar in BexT4+Cil vs. BexT4+ mice. Our data indicates that inhibition of the integrin αVβ3 is an effective strategy to improve Bex-based treatments in CTCL. DisclosuresCerchietti:Celgene: Research Funding; Lymphoma Research Foundation: Research Funding; Leukemia and Lymphoma Society: Research Funding; Weill Cornell Medicine - New York Presbyterian Hospital: Employment.

Delineating the Nuclear Receptors Involved in Retinoid Responsiveness in CTCL Cells

Introduction: Cutaneous T Cell Lymphoma (CTCL) has an annual incidence of one per 6.4 million persons in the United States and represents 3.9% of all non-Hodgkin lymphomas. Numerous treatment modalities exist, including both oral Bexarotene and topical Bexarotene 1% gel. Bexarotene is a synthetic retinoid that selectively activates retinoid X receptor (RXR) isotypes. Retinoids, natural metabolic derivatives and synthetic analogs of vitamin A, are physiologically important in establishing mucosal immunity. Retinoids induce gut homing in T lymphocytes effectively targeting immune cells away from the skin niche. Although it is appreciated that retinoids activate the retinoic acid receptor (RAR) and retinoid X receptor (RXR) family of nuclear receptors to elicit cellular changes, the molecular details of retinoic acid action remain poorly defined within the context of CTCL therapy. The specific nuclear receptor isotypes involved in CTCL responsiveness and if this responsiveness entails the expression of molecules associated with gut homing is not known. The significance of this knowledge gap is championed by the fact that the full benefit of Bexarotene in CTCL is limited due to adverse metabolic side effects, namely, hypercholesterolemia, hypothyroidism, and hyperlipidemia. The promiscuous pairing nature of RXR with other nuclear receptors such as the liver X receptor and thyroid hormone likely accounts for the detrimental effects. Delineating how retinoids influence CTCL at the molecular level would greatly increase the specificity and efficacy of retinoid-based therapies.Results: Here we employ a battery of agonists and antagonists, including Bexarotene, to delineate the specific nuclear receptors utilized by retinoids to evoke adhesion changes within CTCL cells. When a spectrum of T cell lymphomas/leukemias are cultured with the physiologically relevant all-trans-retinoic acid (atRA) retinoid isomer, only CTCL lineages increase integrin-mediated adhesion to the gut trafficking ligand, Mucosal Adressin Cell Adhesion Molecule (MAdCAM-1). Our data further demonstrate that the individual activation of RAR or RXR nuclear receptors isotypes was sufficient to induce adhesion to MAdCAM-1 within the CTCL cells. Our data also establish that the induced immune cell adhesion was largely attributable to the specific activity of the RAR-alpha receptor isotype. However, longer exposure to other isotype-specific agonists did induce adhesion. Most importantly, we show that the adhesion to MAdCAM-1 was significantly augmented upon activation of both RAR and RXR nuclear receptors in a synergistic manner. In addition, this synergism was only observed with the RAR-alpha isotype.Conclusions: The current study provides molecular resolution as to which nuclear receptors transduce retinoid exposure into biologically relevant CTCL cell adhesion. Our work suggests that Bexarotene therapy can be augmented by combinatorial drug therapy with a RAR-alpha agonist to induce synergistic receptor activation. Decreasing the concentration of Bexarotene required to elicit a desired response and increasing the specificity by targeting distinct receptor isotypes would plausible minimize the adverse side effects associated with retinoids. The significance of this work is underscored by the historical success of retinoid-based therapies such as Bexarotene and the potential undiscovered therapies still embodied within vitamin A. DisclosuresNo relevant conflicts of interest to declare.

Experience with bexarotene in cutaneous T-cell lymphoma: A collaborative study of the Spanish Group of Cutaneous Lymphoma

Experience with bexarotene in cutaneous T-cell lymphoma: A collaborative study of the Spanish Group of Cutaneous Lymphoma

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

Background: Bexarotene was approved for cutaneous T-cell lymphoma (CTCL) in 1999. Apart from the two first clinical trials published ten years ago, very few data were published on the long-term use of bexarotene in CTCL patients.Objectives: We performed a retrospective review of CTCL patients treated with bexarotene at a single skin Cancer department between 2002 and 2012. We aimed to determine retrospectively the long-term tolerability and outcome of bexarotene in a cohort of CTCL patients and to compare these results with data from the literature.Results: Thirty-two patients were included (18 men/14 women); 20 patients had a mycosis fungoïdes and 12 a Sézary syndrome. The longest bexarotene treatment duration observed was 65.2 months and 10 patients were treated for more than 24 months. A clinical response was reported in 60% of all patients and in 75% of patients with Sézary syndrome. Most common drug-related adverse events were hypothyroidism (94%), hypertriglyceridemia (78%) and hypercholesterolemia (44%). Most events (84%) were mild to moderate.Conclusions: This study with a very long observation time confirms that bexarotene is well tolerated by CTCL patients during long-term use. It is effective in early and advanced stages of CTCL.

The Combined Safety and Tolerability Profile of Vorinostat-Based Therapy for Solid or Hematologic Malignancies.

Abstract 1710Poster Board I-736 IntroductionTreatment regimens for cancer are typically based on cytotoxic chemotherapy, which is poorly tolerated. There is an unmet medical need for new therapies that retain efficacy, but combine this with an improved safety and tolerability profile. Vorinostat is a histone deacetylase (HDAC) inhibitor, approved in the United States for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients who have progressive, persistent, or recurrent disease on or following 2 systemic therapies. Vorinostat is also being investigated as a treatment for various other solid and hematologic malignancies, in which HDACs are further implicated as key regulators of transcription. Herein we present an overview of the safety and tolerability profile of vorinostat, gathered from prior clinical experience. MethodsSafety and tolerability data, including adverse events (AEs), QTc interval data and incidence of thromboembolic events (TEE), were collated from patients who received vorinostat, administered as monotherapy or in combination therapy for solid or hematologic malignancies. Results (adverse events)In Phase I and II clinical trials, 498 patients who received vorinostat were analyzed. A total of 341 patients received vorinostat monotherapy (107 with CTCL, 105 other hematologic malignancies, 129 solid tumors) and the most common drug-related AEs in this group were: fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%); Grade 3/4 AEs included fatigue (12.0%) and thrombocytopenia (10.6%), and 3 drug-related deaths (ischemic stroke, tumor hemorrhage, unspecified) occurred. Thirty-eight patients (11.1%) discontinued due to drug-related AEs, 71 patients (20.8%) required dose modifications, and 1 patient (0.3%) discontinued due to Grade 2 chest pain. The remaining 157 patients received vorinostat combination therapy (with pemetrexed/cisplatin for advanced cancer [n=46], bortezomib for multiple myeloma [n=34], bexarotene for CTCL [n=23], and erlotinib [n=30], gemcitabine/platin [n=21] or carboplatin/paclitaxel [n=3] for non-small-cell lung cancer). The most common drug-related AEs in this group were: nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), and vomiting (31.2%); the most common Grade 3/4 AE was fatigue (13.4%), and 1 drug-related death (hemoptysis) occurred. Thirty-one patients (19.7%) discontinued due to drug-related AEs and 27 patients (17.2%) required dose modifications. Results (QTcF interval)A trial of 24 patients with advanced cancer was undertaken for rigorous assessment of QTcF interval. In this trial, a single supratherapeutic 800 mg dose of vorinostat did not prolong QTcF interval (monitored over 24 hours). The upper limit of the 90% confidence interval for the placebo-adjusted mean change-from-baseline of vorinostat was <10 msec at every timepoint, no patient had a QTcF change-from-baseline value >30 msec, and 1 patient had a QTcF interval >450 msec (after both vorinostat and placebo administration). The most common drug-related AE in this trial was nausea. There were no serious clinical or laboratory AEs, no discontinuations due to an AE and no patients experienced a cardiac-related AE. Results (incidence of TEE)A review of vorinostat clinical trials, published literature and post-marketing surveillance reports was conducted by a committee of independent academic experts to determine the incidence of TEE in cancer patients who had received vorinostat. In >1845 patients reviewed through November 3, 2008, 107 patients (<5.8%) reported TEE as a serious AE (SAE), 47 (<2.6%) of which were recorded as being related to vorinostat, and 4/47 (<0.3%) TEE SAEs were fatal. ConclusionsIn this review, the majority of observed AEs were 'Grade 2, there was no observed prolongation of the QTcF interval, and the incidence of TEE with vorinostat was similar to reported rates of TEE in advanced cancer patients. Vorinostat is generally well tolerated when administered as monotherapy or in a combination regimen in cancer patients. DisclosuresSiegel:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celegne: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rubin:Merck: Employment, Equity Ownership. Iwamoto:Merck: Employment, Equity Ownership. Hussein:Celgene: Employment. Belani:Merck: Consultancy. Hardwick:Merck: Employment, Equity Ownership. Rizvi:Merck: Employment, Equity Ownership.

Retinol, Vitamins, and Cancer Prevention: 25 Years of Learning and Relearning

Retinol, Vitamins, and Cancer Prevention: 25 Years of Learning and Relearning

The optimal use of bexarotene in cutaneous T-cell lymphoma

The management goal in cutaneous T-cell lymphomas (CTCLs) is to improve symptoms and induce remission. Early-stage disease is generally treated with skin-directed therapies. However, if these do not control the disease, systemic therapy becomes necessary. Bexarotene, a novel rexinoid, is an oral, noncytotoxic drug that has been approved in Europe for the treatment of refractory advanced-stage CTCL and in the U.S.A. for refractory CTCL. We provide guidance on the use of bexarotene in the management of CTCL, based on data from phase II/III clinical trials and the authors' clinical experience, and suggest how the potential of the drug can be maximized. The clinical trial results with bexarotene are reviewed, especially in comparison with interferon-alpha, which is the other commonly used noncytotoxic systemic therapy for CTCL. A treatment algorithm for bexarotene in refractory CTCL is suggested. As bexarotene may take time to achieve a maximum response, this algorithm recommends that therapy should be continued for a sufficient period to allow for a delayed onset of action. In addition, possible combination therapies with bexarotene are discussed. We conclude that bexarotene is effective in the management of CTCL, and has the advantage of oral administration. An on-going randomized clinical trial comparing psoralen plus ultraviolet A (PUVA) with PUVA plus bexarotene will provide valuable information about this combination regimen in early-stage disease, but further data are needed on the relative efficacies of other combination therapies with bexarotene in CTCL.

Minimizing adverse side-effects of oral bexarotene in cutaneous T-cell lymphoma: an expert opinion

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.

Biological Effects of Bexarotene in Cutaneous T-Cell Lymphoma

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.

The Treatment of Cutaneous T-Cell Lymphoma with a Novel Retinoid

The clinical experience with bexarotene for cutaneous T-cell lymphoma (CTCL) at our center is reviewed here. Disease activity assessment was monitored every 4 weeks in all patients. Five target lesions were monitored, an area score was performed, and a CTCL-specific health assessment questionnaire was administered. Four patients with refractory plaque CTCL were treated with bexarotene gel. All target lesions disappeared after 8 weeks of therapy, with recurrences observed in untreated areas. In the follow-up period, no recurrences of the original target lesions were observed. One patient withdrew from the study. Patients with refractory patch/plaque disease were randomized to a high-dose (300 mg/m2) or low-dose (6.5 mg/m2) daily oral regimen of bexarotene. After showing disease progression, the two patients on the low-dose arm were entered into the high-dose arm after 8 weeks. Marked clinical responses were seen in all patients treated. The target lesions showed either complete disappearance or a reduction in lesion size, duration, and scale. No new lesions were noted in patients on high-dose bexarotene. Self-assessments also confirmed the palliative properties of the observed responses. All patients had hypertriglyceridemia despite the concomitant administration of atorvastatin at 60 mg/day. Dose reductions were required to maintain safe lipid levels. Four patients with erythrodermic CTCL were treated with high-dose oral therapy, and all patients showed rapid (within 2 weeks) improvement of erythroderma and symptoms.