Low-dose Bexarotene Research Articles

The Role of ARID1A in the Nonestrogenic Modulation of IGF-1 Signaling.

This study underscores the possibility of the pharmacologic modulation of the ARID1A factor to downregulate protumorigenic IGF-1 activity in patients with postmenopausal breast cancer undergoing aromatase inhibitor treatment.

Safety and efficacy of bexarotene for Japanese patients with cutaneous T-cell lymphoma: Real-world experience from post-marketing surveillance.

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 300mg/m2 (61.6%) and patients who started with bexarotene at less than 300mg/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 300mg/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 300mg/m2 than patients who started with bexarotene at less than 300mg/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 300mg/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.

Case series of cutaneous T-cell lymphomas treated with bexarotene-based therapy.

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. Objectiveresponse rate (ORR) for the overall cohort was 65.5%. ORR of the 300mg/m2 cohort (conventional dose) was 76.2%, while that of the 150-300mg/body (low dose) with narrowband ultraviolet B light (NBUVB) cohort was 37.5%. Mean event-free survival was 10.0months for all patients, 6.7months for the bexarotene conventional-dose cohort and 19.1months 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.

Ten-year Experience of Bexarotene Therapy for Cutaneous T-cell Lymphoma in Finland

Bexarotene is an oral retinoid shown to be active against the cutaneous manifestations of cutaneous T-cell lym-phoma (CTCL). Literature on the efficacy, dosing and side-effects of bexarotene is sparse. We present here data on 37 Finnish patients with CTCL treated with bexarotene during the last 10 years. Bexarotene was equally effective as monotherapy or when combined with other treatment modalities, resulting in overall responses of approximately 75%. Early-stage CTCL responded better than advanced-stage CTCL (83% vs. 33%). The mean time to observable response was 3 months and the mean duration of the response was 21 months. The dose of bexarotene was generally lower than recommended due to side-effects. Abrupt elevation of liver transaminases, resulting in cessation of treatment, was observed in 4 (11%) patients. We conclude that the dose of bexarotene should be titrated individually to achieve optimal results. Maintenance therapy with low-dose bexarotene is a feasible alternative.

Low Dose Bexarotene and Ultraviolet A Photochemotherapy (PUVA) In a Prospective Phase II Clinical Study for Refractory and/or Resistant Cutaneous T Cell Lymphomas (CTCL)

AbstractAbstract 3953Oral bexarotene, a novel retinoid that selectively activates retinoid × receptors, is approved for the treatment of cutaneous manifestations of refractory or relapsed cutaneous T cell lymphomas (CTCL) as monotherapy. Phase II/III trials have demonstrated a greater than 50% response rate in patients with all stages of CTCL who were refractory or intolerant to the previous therapy but the recommended bexarotene dose of 300 mg/m2/day is associated with significant side-effects. Novel studies are looking for synergistic therapies combining lower bexarotene doses in order to reach the same or even better outcomes while avoiding a negative impact on the quality of life. Early studies with bexarotene and psoralen plus ultraviolet A photochemotherapy (PUVA) show promise. Synergy between bexarotene and PUVA may derive from retinoid-induced reductions in epidermal thickness, which consequently improves UVA penetrations, and/or from retinoid-specific enhancement of immune functions. The aim of this study was to assess the efficacy and safety of a 2 stage-protocol (induction and maintenance) with low dose bexarotene (Targretin) and PUVA in refractory and/or resistant patients with Mycosis Fungoides (MF) and Sézary Syndrome (SS).A prospective, phase 2 clinical study was conducted between February 2007 and May 2010 by two Italian academic hospital centers. We enrolled 15 patients with stages I through IV MF/SS; all patients had failed PUVA or several systemic regimens. Response to treatment was assessed with clinical endpoints such as remission of symptoms (pruritus, pain, sleep disturbance) and signs (erythema, scaling, thickness of plaques, presence of nodules, tumours, peripheral lymphadenopathy). Complete remission (CR) was defined as the disappearance of all clinical evidence of disease for at least 4–6 weeks, partial remission (PR) as 50% or more decrease in extent or severity of disease. Overall response (OR) rate was defined as the combination of CR/PR. Patients with MF/SS were started with bexarotene (150 mg/day) and PUVA (three times weekly). Increments of bexarotene to a maximum of 300 mg/day were scheduled. Patients who achieved CRs and PRs during the induction remained on the same dose in the maintenance period, whereas the frequency of PUVA was gradually reduced. A preventive therapy to lower triglycerides and elevated thyroid hormone levels in the blood, was administered in all cases; therapeutic dietary and lifestyle changes were often recommended.Primary endpoint were OR rate at the end of induction and maintenance; secondary endpoints were safety and event-free survival (EFS). Kaplan-Meyer method and long-rank test was used for statistical analysis.All 15 patients (8 M and 7F) were evaluable for response; ten patients had early-stage (IB) and 5 had advanced stage (2 IIB, 1 IIIA, 1 IIIB, 1 IV). The median age was 68 years (34-81). The OR rate was 93% with 33% CR after induction period and 93% with 47% CR at the end of the protocol. A response was observed even in 1 case with SS and in 2 cases with MF in large cell transformation. Significantly, patients treated previously with PUVA monotherapy achieved better and faster CR compared with those treated with more than one systemic therapy (83% and 22% respectively; χ2 test, P=0.041; median time to maximal response 4 weeks and 8 weeks respectively, P=0.007). Median EFS at 37 months, for the whole group was 27 months. All patients have been closely monitored for adverse events during treatment; 2 of 15 patients (13%) had mild grade I-II asthenia, hypercholesterolemia and central hypothyroidism, 2 patients developed elevations of CPK (grade 3). With regard to hematologic toxicity, leukopenia was mild (grade I) and occurred in 3 patients (20%).In conclusion, our study have demonstrated a greater than 90% response rate in patients with all stages of CTCL refractory or intolerant to the previous therapies; the efficacy is more pronounced in patients previously treated with PUVA monotherapy. Starting treatment at lower dose of bexarotene followed by dose escalation may improve the efficacy and safety of both bexarotene and PUVA. Moreover the additional maintenance phase seems to improve the OR and length of remissions. Disclosures:Leoni:Celgene: Honoraria.

Low-Dose Bexarotene Alone or in Combination for the Treatment of Relapsed or Refractory Cutaneous T-Cell Lymphoma.

Abstract 4790 IntroductionSelective ligands of retinoid X receptor (i.e. bexarotene) are used in the treatment of early and advanced stages of cutaneous T-cell lymphoma (CTCL). The objective of this study is to report a Peruvian single-institution experience on 13 cases of relapsed or refractory CTCL who were treated with low-dose bexarotene alone or in combination with phototherapy or interferon alfa-2a. MethodsFrom 2002 to 2008, thirteen patients with relapsed or refractory CTCL were treated with bexarotene at low dose (75-300 mg/day) as monotherapy (BEX; 3 cases) or in combination with interferon alfa-2a (INF) at 3-9 million units subcutaneously three times a week (5 cases) or phototherapy (PT; 4 cases). Therapy was continuously administered until progression of disease or unacceptable toxicity. Eight patients with mycosis fungoides (MF), two patients with aggressive epidermotropic CD8+ cytotoxic lymphoma (AECL), two patients with Sezary Syndrome (SS) and one with smoldering adult T-cell leukemia/lymphoma (ATLL) were included in this study. ResultsMean age was 57 years (range 26 to 74 years). In average, patients were exposed to three prior lines of therapy (range 1 to 5). From the 8 cases of MF, 3 cases were treated with BEX monotherapy, achieving 1 complete response (CR), 1 partial response (PR) and 1 progressive disease (PD); 3 cases were treated with BEX and PT, obtaining 1 CR and 2 PR; and 2 cases were treated with BEX and IFN, both showing PD. From the 2 cases with AECL, 1 case received BEX/PT achieving a PR and 1 case received BEX/IFN showing PD. From the 2 cases with SS, both were treated with BEX/IFN achieving a PR. The case of ATLL achieved a PR with BEX/PT. The overall response for the entire group was 69.2% (9/13) with a mean duration of response of 15 months (range 2 to 67 months). From the therapy point of view, BEX alone achieved a 66% overall response rate (ORR), BEX/IFN showed a 40% ORR and BEX/PT showed a 100% ORR with a 20% CR. Most common adverse events were mild, seven patients experienced grade 1–2 hypercholesterolemia, and hypertriglyceridemia grade 1–2 was seen in seven patients and grade 3 in two cases. Four patients developed grade 1–2 hypothyroidism. ConclusionsLow-dose BEX alone or in combination with INF or PT is effective in the treatment of patients with relapsed or refractory CTCL and is associated with mild toxicity. Prospective studies, if possible, are needed to further investigate novel therapeutic approaches in these hard-to-treat patients. Disclosures:No relevant conflicts of interest to declare.

Low-Dose Bexarotene and Phototherapy or Interferon Alfa-2a in the Treatment of Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma

Background: Selective ligands of retinoid X receptor (i.e. bexarotene) are used in the treatment of early and advanced stages of cutaneous T-cell lymphoma (CTCL). Relapsed or refractory cases of CTCL have poor prognosis and are in need of safe and more effective therapies. Synergy between bexarotene and interferon or phototherapy has been previously described.Objective: Report a Peruvian single-institution experience on eight cases of relapsed or refractory CTCL who were treated with low-dose bexarotene in combination with phototherapy or interferon alfa-2a.Methods: From 2002 to 2007, eight patients with relapsed or refractory CTCL were treated with bexarotene 300 mg by mouth daily in combination with interferon alfa-2a 9 million units subcutaneously three times a week (five patients) or phototherapy (two patients received PUVA therapy and one patient received narrow-wave UVB therapy). Bexarotene, interferon and phototherapy were continuously administered until progression of disease or unacceptable toxicity. Five patients were diagnosed with mycosis fungoides (MF), two patients had aggressive epidermotropic CD8+ cytotoxic lymphoma (AECL) and one patient had Sezary Syndrome (SS).Results: Mean age was 58 years (range 36 to 70). Patients were exposed to three prior lines of therapy in average (range 2 to 5). One patient had complete response, four patients had partial response and three patients experienced progressive disease. The overall response for the entire group was 62.5% with a mean duration of response of 20 months (range 7 to 67 months). Forty percent (2/5) of patients had partial response to the bexarotene and interferon combination; no complete responses were observed. The two responders, one patient with SS and one patient with MF, are alive 67 and 17 months, respectively. On the other hand, 100% (3/3) of patients responded to the bexarotene and phototherapy combination. A patient with stage I MF experienced a complete response and two patients had a partial response, one patient with MF and one with AECL. Of note, the patient who achieved a complete response was treated with bexarotene and narrow-wave UVB. Most commonly side effects observed were mild, five patients experienced grade 1–2 hypercholesterolemia, hypertriglyceridemia grade 1–2 was seen in four patients and grade 3 in one case. Two patients developed grade 1–2 hypothyroidism. Our patient with SS developed cardiomyopathy related to interferon after 17 months of therapy and continues on single-agent bexarotene. The use of bexarotene in the treatment of AECL has seldom been reported. We are also reporting one of the longest lasting responses described in a patient with SS treated with bexarotene.Conclusions: Low-dose bexarotene in combination with phototherapy or interferon alfa-2a in the treatment of relapsed and refractory CTCL seems safe and effective. Further research is necessary to develop improved, more effective therapies.Table 1. Characteristics of reported patientsAgeSexHistologyStageNumber previous treatmentsTreatmentResponseDuration response (months)Bexarotene/interferonBexarotene/phototherapy69FSS-2XPR6761MMFIII2XPR1736FAECLIB4XPD-70FMFIIB2XPD-57MMFIIB5XPD-44MMFIB2XCR1759MMFIIB2XPR767MAECLIIB3XPR12F: female; M: male; SS: Sezary syndrome; AECL: aggressive epidermotropic CD8+ cytotoxic lymphoma; MF: mycosis fungoides; PR: partial response; CR: complete response; PD: progressive disease

Multicenter Trial of Photopheresis in Early Stage Mycosis Fungoides

Extracorporeal photopheresis (ECP) has been approved for 20 years for patients with erythrodermic MF or Sézary syndrome (SS) with circulating atypical T-cells. The response rate of 54% was based on 25% improvement in erythema. ECP has not widely been used to treat patients with early stage MF. The objective of this multicenter single-arm open-label study was to determine the efficacy of UVAR® XTSÔ Photopheresis System in early stage MF with measurable skin lesions. Patients were eligible at stage IA if there was with minor blood involvement (B1), or at IB- IIA MF with or without minor blood involvement (B1). Patients had to be refractory to at least one treatment for early MF such as PUVA, electron beam, oral or topical high potency steroids, topical mustragen, oral methotrexate, alpha interferon, or bexarotene. Two photopheresis treatments were given on successive days every 4 weeks for six months. There were 13 evaluable patients treated with ECP (4 males/9 females; 12 Caucasians, 1 African-American) whose median age was 61 yrs (range 46–85). Their stages were IA (n=3), IB (n=8) and IIA (n=2). Patients received a median of 12 ECP sessions (range 4–42+) over a median of 6 months (range 5–22). The overall response rate of 54% (7 of 13) required a ≥50% improvement in the baseline body surface area involved with patches or plaques. The median time to response was 6 months (range 3–8 months) and median duration of response was 6 mos (range 2–30 mos). The protocol allowed additional therapy if patients failed to improve by month 3. ECP alone was effective in four of ten patients (40%) and the other three patients had partial response with combined therapy: two with low dose bexarotene (150 mg) added at 4 or 6 mos and a third with bexarotene, interferon, and PUVA at 6 mos. Only 2 of 13 patients progressed and four had stable disease. There were no photopheresis related adverse events other than mild post-ECP erythema in one patient. One patient developed central right arterial occlusion with left eye visual defect unrelated to the ECP. In conclusion, photopheresis had a 54% response rate for all 13 patients and a 40% response rate to ECP alone in 10 early stage MF patients without adverse side effects suggesting it could be successfully used to treat early MF patients.

Low-dose bexarotene combined with psoralen plus UVA (PUVA) is associated with an encouraging response in patients with mycosis fungoides

Low-dose bexarotene combined with psoralen plus UVA (PUVA) is associated with an encouraging response in patients with mycosis fungoides

Low-dose bexarotene, as add-on to antipsychotic treatment in patients with schizophrenia, is effective and well tolerated,

Low-dose bexarotene, as add-on to antipsychotic treatment in patients with schizophrenia, is effective and well tolerated,

Safety and Efficacy of Low-Dose Bexarotene and PUVA in the Treatment of Patients with Mycosis Fungoides

The new rexinoid bexarotene is a retinoid X receptor antagonist and immune response modifier. Although combinations of oral bexarotene and psoralen plus UVA (PUVA) have been tried in patients with all stages of mycosis fungoides (MF), the dosage of bexarotene used in these combination regimens has been variable. To assess the efficacy and safety of low-dose oral bexarotene and PUVA in patients with relapsed or treatment-refractory MF following monotherapy with multiple agents including PUVA, narrow-band UVB, interferon-alpha, oral bexarotene, and topical corticosteroids. Combination therapy with PUVA three times weekly and low-dose oral bexarotene (150 or 300 mg/day, depending on physicians' preference) was administered to 14 patients, seven men and seven women (median age 49.5 years, range 30-75 years), with relapsed or refractory MF stages I-III. All responders received maintenance treatment at the same bexarotene dose that induced remission until progression or unacceptable toxicity. Low-dose oral bexarotene combined with PUVA was associated with an overall response rate (complete response or partial response) in 67% of the nine patients with refractory MF who completed the treatment course. Of these nine patients, four had a complete response, two had a partial response, one had stable disease, and two had progressive disease. Five patients withdrew because of hyperlipidemia. Oral bexarotene was continued as maintenance therapy in three of the four complete responders (one refused); two of these patients relapsed 2-10 months after PUVA discontinuation. Patients with partial response or stable disease received the combination for 3-5 months and were switched to another treatment regimen because of lack of further response. Therapy was fairly well tolerated. In a select population of patients who had not responded to at least one monotherapy for early-stage MF, a combination of low-dose oral bexarotene and PUVA was successful in achieving a satisfactory overall response rate in 67% of patients who completed the treatment course and was fairly well tolerated. Limitations of the study include the small number of patients evaluated, its retrospective nature, and the fact that patients were commenced on different bexarotene starting doses (150 or 300 mg/day), depending on physicians' preference.

Low-dose oral bexarotene in combination with low-dose interferon alfa in the treatment of cutaneous T-cell lymphoma: clinical synergism and possible immunologic mechanisms

BackgroundFor 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/m2 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. ObservationsWe 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. ConclusionsCombining 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.