Alitretinoin in the treatment of cutaneous T-cell lymphoma.

INTRODUCTION: In this survey, we analyzed data from patients suffering from the most common cutaneous T-cell lymphomas (CTCLs) subtypes mycosis fungoides (MF) and Sézary syndrome (SS), treated with the retinoid alitretinoin during a 7-year period at our outpatient department between 2015 and 2020. MATERIALS AND METHODS: We analyzed patient medical records including TNMB stage, side effects under therapy with alitretinoin, time to next treatment (TTNT), and previous photo documentation. RESULTS: A total of 35 patients with MF (n = 28) and SS (n = 7) were included in the study, of whom 69% were male and 31% were female. The mean age of onset was 56 ± 15 years in MF and 65.4 ± 10.8 years in SS with 51.4% having early stage (IA-IIA) and 48.6% having advanced stage (IIB-IVA) CTCL. Of these patients 37.2% responded to alitretinoin, 28.6% had a stable course, and 34.3% experienced progression. Alitretinoin was administered as a monotherapy (25.7%) or combined with five concomitant therapies (74.2%), most frequently with ECP (31.4%) and PUVA (11.4%). 63% did not report any side effects, most often hypertriglyceridemia (20%) was described. CONCLUSION: Considering that nearly two thirds of the CTCL patients treated with alitretinoin showed a response or stable disease, together with a low number of side effects and low cost compared to bexarotene, alitretinoin may be a potential alternative in the treatment of less advanced CTCLs. This survey represents the largest number of recorded therapies with the retinoid alitretinoin in CTCLs in a European patient collective.

Alemtuzumab is an effective third-line treatment versus single-agent gemcitabine or pralatrexate for refractory Sézary syndrome: a systematic review.

The efficacy of alemtuzumab for the treatment of refractory Sézary syndrome (SS) versus other third-line agents such as pralatrexate and gemcitabine is poorly characterized. To elucidate the effectiveness of alemtuzumab versus other third-line options for the treatment of refractory SS, we conducted a meta-analysis of existing data. A systematic review was performed in March 2017 based on a search using Ovid-MEDLINE® and OVID-EMBASE® for articles evaluating single-agent alemtuzumab, gemcitabine, or pralatrexate for the treatment of SS and mycosis fungoides (MF). Twenty-two publications were identified that fulfilled all search criteria (total n = 323 patients), with six publications of lower quality being excluded from our analysis in order to decrease the risk of bias (final: n = 308 patients; 93 with SS and 147 with MF). Across all studies, alemtuzumab was significantly more effective in patients with SS (overall response rate [ORR]: 81%; complete response rate [CRR]: 38%) than patients with MF (ORR: 29%; CRR: 8%). However, gemcitabine was more effective than alemtuzumab or pralatrexate in treating MF. Alemtuzumab-treated patients had more frequent side effects, which were influenced by route of administration and dose. There was a lower incidence of lymphopenia and other serious adverse events in patients treated with subcutaneous (38%) compared to intravenous regimens (68%), and lower-dose (5%) compared to high-dose alemtuzumab regimens (54%). No significant differences were found in the effectiveness of different routes of administration or dosing regimens. Our review supports the use of low-dose subcutaneous alemtuzumab as a third-line treatment for SS.

Cutaneous T-Cell Lymphoma: A Review with a Focus on Targeted Agents.

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of extranodal lymphomas involving the skin. Diagnosis of the two main subtypes of CTCL-mycosis fungoides (MF) and Sézary syndrome (SS)-is based on the International Society for Cutaneous Lymphomas/European Organization for Research and Treatment of Cancer (ISCL/EORTC) classification system, which utilizes clinical, histopathological, molecular biologic, and immunopathologic features. Risk stratification, based on TNMB (tumor, node, metastasis, and blood) staging, provides prognostic information, with limited-stage disease conferring the longest median overall survival. Skin-directed therapies are preferred in the management of limited-stage disease, whereas advanced-stage disease requires systemic therapies. As the mechanisms of CTCL pathogenesis are increasingly understood, new monoclonal antibodies, checkpoint inhibitors, immunomodulatory agents, and small molecules are under investigation and may provide additional therapeutic options for those with advanced CTCL. This review examines the current landscape of targeted therapies in the treatment of CTCLs.

[Thyroid and lipidic dysfunction associated with bexarotene in cutaneous T-cell lymphoma]. / Disfunción tiroidea y lipídica asociada a bexaroteno en el linfoma cutáneo de células T.

BACKGROUND AND OBJECTIVE: Bexarotene is a synthetic selective X receptor rexinoide approved for the systemic treatment of cutaneous T-cell lymphoma. During treatment is very frequent the occurrence of hypothyroidism and severe mixed hyperlipidemia, both are reversibles and dose-dependent adverse events. Increase of triglycerides and LDL-cholesterol level (up to even higher levels have been associated with pancreatitis in some cases) is widely described (as is the case with other retinoids) but decrease in HDL-cholesterol is poored know. We review our experience with the use of bexarotene. MATERIAL AND METHODS: We present a serie of 3 clinical report of patients treated with bexarotene in whose, in addition to these well-known adverse event, a serious lowering of HDL-cholesterol was observed. RESULTS: The 3 patients studied had metabolic complications like central hypothyroidism and severe mixed hyperlipidemia; with special emphasis on the sharp fall (mean decrease>83%) in the HDL-cholesterol level. Cholesterol lowering medication and substitutive hormonal replacement with levotiroxine resulted in an improvement of the biochimical parameters without reaching the correct goals. CONCLUSIONS: Bexarotene produce as predictable side effects severe mixed hyperlipidemia with marked decrease in HDL-cholesterol levels and central hypothyroidism, being the both reversible and dose-dependent. A reflection on the possible aetiological mechanisms and implications of this phenomenon are included.

Skin-Directed Therapies in Cutaneous T-Cell Lymphoma.

Early stage mycosis fungoides represents the most common clinical presentation of cutaneous lymphoma, with skin-directed therapies long established in its treatment. These therapies continue to change as new treatment regimens emerge. Other skin-directed treatments include light and radiation therapy. Therapies with higher levels of evidence and less systemic toxicity are usually preferred as first-line treatment. However, even these established therapies, like topical corticosteroids and carmustine, lack randomized clinical trials to establish their efficacy. Research is also needed to further define the role of combination topical therapies and how skin-directed therapies can be used as adjuvants to systemic medications.

The Role of Systemic Retinoids in the Treatment of Cutaneous T-Cell Lymphoma.

Retinoids are natural and synthetic vitamin A analogs with effects on cell proliferation, differentiation, and apoptosis. They have significant activity in hematologic malignancies and have been studied extensively in cutaneous T-cell lymphoma. Retinoids bind to nuclear receptors and exert their effects through moderation of gene expression. Retinoic acid receptor and retinoic X receptor exert regulatory activity in vivo, binding to distinct ligands. Studies investigating systemic retinoids as monotherapy and in combination with other agents active against cutaneous lymphoma are reviewed. Side effects associated with retinoids include teratogenicity, dyslipidemias, and hypothyroidism, which should be carefully monitored in patients receiving treatment.

CD30 As a Target for the Treatment of Cutaneous T-Cell Lymphoma.

A 72-year-man presented with a 7-month history of progressive patches and plaques over the trunk and limbs. A skin biopsy confirmed mycosis fungoides (MF). After staging investigations, he was considered to have T2N0M0B0 (stage Ib) disease and began ultraviolet (UV) B phototherapy. Despite initial response, his disease progressed after 4 months, with enlarging patches and plaques but without nodal involvement. As second-line therapy, he received interferon alfa-2b (IFN--2b) 2.7 MU daily, which he tolerated well. He again experienced initial partial response (PR), but by 18 months, he had experienced tumor progression, with patches, plaques, and multiple tumors over the body (up to 3 cm; Fig 1). Biopsy of a neck tumor demonstrated tumor-stage MF,with no evidence of large-cell transformation. Approximately 30% of lymphocytes strongly expressed CD30. CD25 was negative. He began treatment with oral methotrexate 20mg per week, which he tolerated well, and achieved a PR lasting 7 months before multiple plaque and tumor lesions recurred, along with the development of inguinal lymphadenopthy. Biopsy of the skin lesions confirmed the same disease, and [18F]fluorodeoxyglucose­positron emission tomography demonstrated avidity in inguinal and internal iliac nodes, with lymphadenopathy measuring up to 3.5 cm. He has been referred for consideration of further systemic therapy.

Treatment of Sézary Syndrome With Alemtuzumab: A Series of 5 Cases and a Review of the Literature.

Alemtuzumab is a monoclonal antibody that has been used to treat refractory cases of Sézary syndrome (SS) and advanced mycosis fungoides. We present 5 patients with SS who were treated with alemtuzumab between 2008 and 2012, with an overall response rate of 80% (40% partial response and 40% complete response). A regimen of 10mg administered subcutaneously was well tolerated with acceptable toxicity. The median duration of response was 13 months. However, one patient remains in complete remission after 67 months, a remarkable outcome given the low survival rate associated with SS. In conclusion, we believe that alemtuzumab may be useful in cases of SS refractory to other treatments. As there are no curative treatments for SS, alemtuzumab should be considered as a therapeutic option.

Treatment of cutaneous T-cell lymphoma with oral alitretinoin.

BACKGROUND: Cutaneous T-cell lymphoma (CTCL) is a potentially life-limiting malignant disease. Treatment strategies in CTCL aim at disease control and remission with the lowest possible side-effects. OBJECTIVE: Recent reports suggest that the new vitamin A derivative alitretinoin might be a well-tolerated treatment option. METHODS: We analysed the files of 11 CTCL patients with mycosis fungoides (n = 10) or Sézary syndrome (n = 1), who were treated with oral alitretinoin alone or in combination with standard treatment based on individual off-label treatment decisions. Patients had been monitored every 4-8 weeks with skin examination and laboratory analyses. RESULTS: Ten of 11 patients (90.9%) showed a marked improvement of their CTCL skin lesions and no progress of the disease during treatment with alitretinoin, one patient showed no response to the treatment (9.1%). Four of the responding patients (40.0%) had a complete response and 6 (60.0%) had a partial response. Average time to response was 2.5 months. Duration of treatment varied depending on whether patients had reached complete or partial remission. In general, alitretinoin was well tolerated. One of 11 patients developed high non-fasting average serum cholesterol (>300 mg/dL) and 1/11 a mean non-fasting triglyceride value >500 mg/dL. In 3/11 patients, thyroid-stimulating hormone declined without clinical symptoms during treatment, with one of the patients also showing a decreased thyroxin level. CONCLUSION: In our group of CTCL patients we noticed a low rate of side-effects and an overall good clinical response to treatment with alitretinoin. Further studies are required to substantiate this early clinical observation.

New and established treatment options for mycosis fungoides and Sézary syndrome - an update.

At the time of diagnosis primary cutaneous lymphomas are limited to the skin. T-cell lymphomas represent at least two thirds of all primary cutaneous lymphomas with mycosis fungoides and Sézary syndrome being the most frequent entities. A precise staging based on clinical, histological, immunohistological and molecular biological criteria is crucial for selecting the appropriate therapy. Since curative treatment is only possible in exceptional cases, the aim of any therapy is to achieve healing of the skin lesions, minimizing relapses, preventing progression and maintaining the quality of life. While in early disease stages skin-directed therapy is being used, in later stages systemic treatments become more important. This work aims to provide an overview of established and new therapies for the treatment of mycosis fungoides and Sézary syndrome.

Acitretin for the treatment of cutaneous T-cell lymphoma.

BACKGROUND: Bexarotene is the only Food and Drug Administration-approved retinoid for the treatment of cutaneous T-cell lymphoma (CTCL) and is associated with a relatively high frequency of adverse effects. Acitretin has anecdotally been reported to be effective for CTCL. OBJECTIVE: We sought to determine the effectiveness and tolerability of acitretin as primary or adjuvant therapy for CTCL. METHODS: We conducted a retrospective chart review of patients with CTCL treated with acitretin at a single tertiary care center. RESULTS: A total of 32 patients with CTCL were included: 29 had mycosis fungoides, 2 had Sézary syndrome, and 1 had CTCL not otherwise specified. Median patient age was 55 years; 56% were male; 47% were white, 47% black, and 6% other. In all, 3% of patients were stage IA, 69% stage IB/IIA, 16% stage IIB, 6% stage III, and 6% stage IV. Six patients received acitretin alone; 26 received acitretin in addition to another CTCL therapy. The overall response rate was 59%. In all, 25% of patients had stable disease and 16% had progressive disease. Median duration of response was 28 months. Adverse effects were generally mild with 5 patients discontinuing therapy because of these. LIMITATIONS: In this small retrospective chart review, many patients were on other CTCL therapies while on acitretin; therefore precise assessment of response to acitretin alone was difficult. CONCLUSIONS: Acitretin is well tolerated and potentially effective for early-stage CTCL. Response to acitretin, either as adjuvant therapy monotherapy, is comparable with the response to oral agents currently approved for this disease.

[New developments in Sézary syndrome]. / Actualités sur le syndrome de Sézary.

Sézary syndrome (SS) represents 3% of cutaneous T-cell lymphomas (CTCL). It is an aggressive epidermotropic CTCL with a 5-year survival rate of 24%. According to EORTC (European organization for research and treatment of cancer), SS is defined by erythroderma, diffuse lymphadenopathy, atypical T lymphocytes (>1000/mm(3)), and the presence of a major blood, cutaneous and nodal T cell clone. A specific marker for atypical tumoral T lymphocytes known as Sézary cells was identified in 2001, namely KIR3DL2 (CD158k) receptor, which allows more specific diagnosis of SS; levels of this marker are highly correlated with the clinical course of the disease. In therapeutic terms, clinical trials are being conducted on new molecules that point towards an improved prognosis for this disease. We propose a review of Sézary syndrome, which is currently the subject of scientific papers concerning both physiopathology and therapeutics, with new prospects of targeted therapy.

Cutaneous T-cell lymphoma cells are sensitive to rapamycin.

Cutaneous T-cell lymphomas (CTCL) are characterised by clonal expansion of helper T lymphocytes that infiltrate the skin. Only a small number of cell lines exist to study cellular pathways leading to T-cell transformation and to identify new targets for intervention. We wanted to investigate the inhibition of mTOR as a possible therapeutic target in CTCL. Primary cells of patients with Sézary syndrome (SS) and conventional CTCL cell lines were analysed. Constitutive activation of mTOR was found, and concomitantly, we could show that rapamycin, a specific inhibitor of mTOR, inhibits CTCL cell growth in vitro by induction of cell cycle arrest. Using a previously established animal model for CTCL, we additionally observed upon rapamycin treatment tumor growth inhibition in vivo. In summary, primary cells from patients with SS as well as CTCL cell lines allowed us to identify mTOR as an important target for intervention.

Combination therapy with extracorporeal photopheresis, interferon-alpha, PUVA and topical corticosteroids in the management of Sézary syndrome.

BACKGROUND: Extracorporeal photopheresis (ECP) is recommended for the treatment of Sézary syndrome (SS), the leukemic variant of cutaneous T-cell lymphoma (CTCL). Several combination therapies are used to increase response rates to ECP. PATIENTS AND METHODS: We report our experience with the combination therapy of ECP, interferon-alpha, PUVA and topical corticosteroids in SS. RESULTS: The treatment outcome in 12 SS patients was retrospectively analyzed and showed an overall response rate to this combination treatment of 42 % with 4/12 patients achieving a partial remission and 1/12 patients a stable disease. The median overall survival time was 42 months. We investigated several clinical and laboratory parameters as an indicator for a response to treatment in our patient cohort. A combined analysis of the erythroderma assessment scale, WBC, LDH, CD4/CD8 ratio and the number of Sézary cells revealed that a reduction of several parameters significantly correlated with response to treatment. The parameters which correlated best with response were number of Sézary cells, CD4/CD8 ratio and WBC. CONCLUSIONS: The investigated combination therapy was effective and well-tolerated in a subgroup of SS patients but needs to be evaluated in a larger patient population.

Alemtuzumab for relapsed and refractory erythrodermic cutaneous T-cell lymphoma: a single institution experience from the Robert H. Lurie Comprehensive Cancer Center.

We present the results of an open-label clinical trial and the clinical use of alemtuzumab in 19 heavily pretreated patients with advanced erythrodermic cutaneous T-cell lymphomas (CTCL) (erythrodermic mycosis fungoides and Sézary syndrome). Ten patients received alemtuzumab intravenously using an escalating dose regimen with a final dose of 30 mg three times weekly for 4 weeks followed by subcutaneous administration for 8 weeks. Nine patients were treated with only the SQ or IV dosing. The overall response rate was 84%, with 9 (47%) complete and 7 (37%) partial remissions. The median follow-up was 24 months (range, 6 to 62+ months). Median overall survival was 41 months whereas median progression free survival was 6 months. Minimal residual disease by T-cell gene rearrangement studies was detected in 11 patients who achieved complete response and partial response. Toxicities included myelosuppression and infections; however, the majority of side effects were of Grade 2 in severity and transient. One patient was diagnosed with a concurrent lymphoma (mantle cell lymphoma) 6 months after completing alemtuzumab therapy. Alemtuzumab is particularly effective in patients with erythrodermic CTCL with acceptable toxicities. Combined strategies with alemtuzumab may achieve molecular remissions with longer response durations.

Bexarotene blunts malignant T-cell chemotaxis in Sezary syndrome: reduction of chemokine receptor 4-positive lymphocytes and decreased chemotaxis to thymus and activation-regulated chemokine.

The malignant cells in Sezary syndrome express the skin trafficking molecules' cutaneous lymphocyte associated antigen (CLA) and chemokine receptor 4 (CCR4). High levels of the CCR4 ligand, thymus, and activation-regulated chemokine (TARC), have been reported in the blood and skin of patients. The rexinoid X-receptor specific retinoid, bexarotene, has contributed to the resolution of cutaneous disease among patients. To evaluate the effects of bexarotene on skin trafficking molecule expression and chemotaxis, peripheral blood mononuclear cells from Sezary syndrome patients and healthy controls were treated with bexarotene in vitro. CCR4 and CLA expression levels and chemotaxis in response to TARC (6.25 ng/ml) were evaluated among lymphocytes before and after treatment with bexarotene (10 microM). Flow cytometric analysis was performed to evaluate CD4, CD26, CLA, and CCR4 cell surface expression. Transwell migration assays were performed to evaluate chemotaxis to TARC. Prior to treatment, malignant cells exhibited higher CCR4 expression (45-90%) and greater than four times more chemotaxis to TARC compared with healthy controls. After treatment with bexarotene for 36-96 hr, a 28% reduction in CCR4 expression was noted (P < 0.05) among the malignant population with an associated 9% decrease in chemotaxis to TARC (P < 0.05). Our results show that bexarotene may inhibit malignant cell trafficking to the skin through an ability to suppress CCR4 expression among Sezary syndrome lymphocytes.

The effect of psoralen plus ultraviolet A in vitro in HUT-78 enhances by 5-aminolevulinic acid.

BACKGROUND: Sezary syndrome and mycosis fungoides are forms of cutaneous T-cell lymphoma, and in the early stage of these diseases psoralen plus ultraviolet A (PUVA) is one of the treatments of choice. Photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) is an effective, non-invasive, and safe treatment for most superficial skin cancers. In order to obtain greater efficacy of PUVA, we investigated the synergistic anti-tumor effects of ALA-PDT and PUVA using 8-methoxypsoralen (8-MOP) and a UVA lamp. METHODS: The in vitro effects of PUVA and ALA-PDT and their combination in HUT-78 cell line from human SS were determined by MTT assay. RESULTS: In our results, cell proliferation compared with controls was inhibited to 53.2% with UVA alone, 52.3% with 1 microM 8-MOP, 43.8% with 100 microM ALA, and 19.2% with combined 8-MOP and ALA. CONCLUSION: Combined use of ALA and PUVA using 8-MOP and UVA lamps, which are widespread in Japan, had a strong anti-tumor effect in vitro. Combined treatment with ALA-PDT and PUVA using a UVA lamp appears to have a strong treatment effect.

Systemic monotherapy vs combination therapy for CTCL: rationale and future strategies.

There are few approved therapies for cutaneous T-cell lymphoma (CTCL). The retinoids are the major biologic response modifiers used in CTCL, producing good response rates but few complete responses. For patients with early-stage disease, the oral retinoids can be combined with other therapies, such as psoralen plus ultraviolet A or interferon alpha, to improve response rates. Combined-modality therapy with oral retinoids, combined chemotherapy, electron-beam therapy, and topical mustargen has also proved effective. For the treatment of advanced-stage disease, the targeted therapy denileukin diftitox (Ontak) provides a nonimmunosuppressive alternative to conventional chemotherapy or radiation therapy. Of the conventional chemotherapies that have been tested in CTCL, gemcitabine (Gemzar) has demonstrated good efficacy in producing responses, particularly in patients with tumors. This agent can be used in combination with a maintenance therapy of bexarotene (Targretin) to manage the plaques and patches of mycosis fungoides. Several other targeted therapies are now also in testing, for example, alemtuzumab (CamPath), HuMax-CD4, several histone deacetylase inhibitors, and the transition-state inhibitor forodesine. These drugs, in combination with currently used therapies, may increase the number and combinations of therapies available for the treatment of this chronic condition to optimize long-lasting responses in CTCL.

Clinical experience: practical management of five patients with cutaneous T-cell lymphoma (CTCL)-related symptoms.

There are now a wide variety of therapeutic options for managing patients with cutaneous T-cell lymphoma-related symptoms. These include skin-directed therapies such as psoralen with UVA irradiation (PUVA), topical chemotherapies such as mechlorethamine (nitrogen mustard) and carmustine (BCNU), electron beam radiation, and systemic therapies such as chemotherapy, photopheresis, and interferons. Although treatment algorithms exist for patients with early stage disease, often treatments are individualized, based on patient specific factors, cost, and accessibility of referral centers for specialized therapies. This article provides details of five real-life case studies to illustrate how cutaneous T-cell lymphoma management can be tailored to the needs of each individual patient.