EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - Update 2023.

On behalf of the EORTC Cutaneous Lymphoma Tumours Group (EORTC-CLTG) and following up on earlier versions published in 2006 and 2017 this document provides an updated standard for the treatment of mycosis fungoides and Sézary syndrome (MF/SS). It considers recent relevant publications and treatment options introduced into clinical practice after 2017. Consensus was established among the authors through a series of consecutive consultations in writing and a round of discussion. Treatment options are assigned to each disease stage and, whenever possible and clinically useful, separated into first- and second line options annotated with levels of evidence. Major changes to the previous version include the incorporation of chlormethine, brentuximab vedotin, and mogamulizumab, recommendations on the use of pegylated interferon α (after withdrawal of recombinant unpegylated interferons), and the addition of paragraphs on supportive therapy and on the care of older patients. Still, skin-directed therapies are the most appropriate option for early-stage MF and most patients have a normal life expectancy but may suffer morbidity and impaired quality of life. In advanced disease treatment options have expanded recently. Most patients receive multiple consecutive therapies with treatments often having a relatively short duration of response. For those patients prognosis is still poor and only for a highly selected subset long term remission can be achieved with allogeneic stem cell transplantation. Understanding of the disease, its epidemiology and clinical course, and its most appropriate management are gradually advancing, and there is well-founded hope that this will lead to further improvements in the care of patients with MF/SS.

Immunotherapy for Cutaneous T-Cell Lymphoma: Current Landscape and Future Developments.

Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic, progressive primary cutaneous T-cell lymphomas (CTCLs) for which there are no curative treatments. Skin-directed therapies, such as phototherapy, radiation therapy, or topical nitrogen mustard, provide only short-term remissions. Numerous attempts with different chemotherapeutic regimes failed to achieve meaningful clinical responses. Immunotherapy seems to be a promising avenue to achieve long-term disease control in CTCL. There is compelling evidence indicating that MF and SS are immunogenic lymphomas, which can be recognized by the patient's immune system. However, CTCL uses different strategies to impair host's immunity, eg, via repolarizing the T-cell differentiation from type I to type II, recruiting immunosuppressive regulatory T-cells, and limiting the repertoire of lymphocytes in the circulation. Many currently used therapies, such as interferon-α, imiquimod, extracorporeal phototherapy, and allogeneic bone marrow transplant, seem to exert their therapeutic effect via activation of the antitumor cytotoxic response and reconstitution of the host's immune system. It is likely that novel immunotherapies such as immune checkpoint inhibitors, cancer vaccines, and chimeric antigen receptor-T cells will help to manage CTCL more efficiently. We also discuss how current genomic techniques, such as estimating the mutational load by whole genome sequencing and neoantigen calling, are likely to provide clinically useful information facilitating personalized immunotherapy of CTCL.

Prescribing Home Narrowband UVB Phototherapy: A Review of Current Approaches.

Conventional, full-body phototherapy equipment is costly and therefore patients are usually treated in dermatology centres. Such office-based therapy is often not feasible for those patients who live far away from a phototherapy centre due to lost time and wages, inability to travel because of extensive skin disease, or prohibitive travel costs. Home phototherapy has emerged as a modality that meets the needs of those patients. Our aim was to review available studies on UV sources, treatment protocols, efficacy, and safety of home phototherapy. A literature review was conducted on PubMed using the terms "home" AND "phototherapy" AND ("guide" OR "approach" OR "review" OR "protocol"). From the data extracted, narrowband UVB (311 nm) offers the best balance between safety and efficacy and is recommended for home phototherapy by most authors. Treatment is safe and possible adverse effects are related to overexposure (erythema, blistering). The usual treatment protocol was administering treatments on alternating days, including weekends, with dosing based on the patient's Fitzpatrick skin type. We also provide information on the available home phototherapy systems in Canada and their reimbursement. Home phototherapy is underused in Canada. Narrowband UVB phototherapy sources equipped with a 3-dimensional panel provides a practical and safe option.

Approach to the Assessment and Management of Adult Patients With Atopic Dermatitis: A Consensus Document. Section IV: Treatment Options for the Management of Atopic Dermatitis.

The objectives of therapy for atopic dermatitis (AD) are to reduce skin inflammation and pruritus, restore skin barrier function, and improve quality of life (QoL). Treatments can be classified as moisturizing and basic care, topical therapy, phototherapy, and systemic therapy. In this review, we summarize the treatments for AD and recommendations for their use.

European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - Update 2017.

In order to provide a common standard for the treatment of mycosis fungoides (MF) and Sézary syndrome (SS), the European Organisation for Research and Treatment of Cancer-Cutaneous Lymphoma Task Force (EORTC-CLTF) published in 2006 its consensus recommendations for the stage-adapted selection of management options for these neoplasms. Since then, the understanding of the pathophysiology and epidemiology of MF/SS has advanced, the staging system has been revised, new outcome data have been published and novel treatment options have been introduced. The purpose of the present document is to update the original recommendations bearing in mind that there are still only a limited number of controlled studies to support treatment decisions for MF/SS and that often treatment is determined by institutional experience and availability. This consensus on treatment recommendations was established among the authors through a series of consecutive consultations in writing and a round of discussion. Recommended treatment options are presented according to disease stage, whenever possible categorised into first- and second-line options and supported with levels of evidence as devised by the Oxford Centre for Evidence-Based Medicine (OCEBM). Skin-directed therapies are still the most appropriate option for early-stage MF, and most patients can look forward to a normal life expectancy. For patients with advanced disease, prognosis is still grim, and only for a highly selected subset of patients, prolonged survival can be achieved with allogeneic stem cell transplantation (alloSCT). There is a high need for the development and investigation in controlled clinical trials of treatment options that are based on our increasing understanding of the molecular pathology of MF/SS.

Psoralen with ultraviolet A-induced apoptosis of cutaneous lymphoma cell lines is augmented by type I interferons via the JAK1-STAT1 pathway.

BACKGROUND: Photochemotherapy with psoralen and ultraviolet A (PUVA), with or without adjuvant interferon-α (IFN-α), is a first-line therapy for early-stage mycosis fungoides and other forms of cutaneous T-cell lymphoma (CTCL). However, the mechanism by which PUVA with IFN-α work in CTCL is poorly understood. PURPOSE: To develop a model to investigate the mechanisms of PUVA and PUVA with IFN-α in CTCL cells. METHODS: An in vitro model to study the molecular mechanisms of PUVA was created using two different CTCL cell lines, MyLa, which has functional p53, and HuT-78, in which p53 is inactivated due to a homozygous nonsense mutation. RESULTS: PUVA caused G2/M cell cycle block and apoptosis of MyLa and HuT-78 accompanied by increase in the expression of the mitochondrial pro-apoptotic genes Bax, BAK, and PUMA and a downregulation in anti-apoptotic Bcl-2. p53 was induced and c-Myc was repressed by PUVA, but neither were essential for PUVA-induced apoptosis. IFN-α augmented PUVA-induced apoptosis via the JAK1 pathway, and this activity could be inhibited by ruxolitinib. CONCLUSION: PUVA induces p53-independent apoptosis in CTCL cell lines, and this process is augmented by type I interferons via the JAK1 pathway.

Small-molecule inhibitors of Ataxia Telangiectasia and Rad3 related kinase (ATR) sensitize lymphoma cells to UVA radiation.

BACKGROUND: Psoralen plus ultraviolet A (PUVA) photochemotherapy is a combination treatment used for inflammatory and neoplastic skin diseases such as mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma (CTCL). However, 30% of MF patients do not respond sufficiently to PUVA and require more aggressive therapies. OBJECTIVE: The aim of this project was to investigate whether inhibition of Ataxia Telangiectasia and Rad3 related kinase (ATR) may enhance efficacy of phototherapy. METHODS: CTCL cell lines (MyLa2000, SeAx and Mac2a) served as in vitro cell models. ATR and Chk1 were inhibited by small molecule antagonists VE-821, VE-822 or Chir-124, or by small interfering RNAs (siRNAs). Cell cycle and viability were assessed by flow cytometry. RESULTS: Small molecule inhibitors of ATR and Chk1 potently sensitized all cell lines to PUVA and, importantly, also to UVA, which by itself did not cause apoptotic response. VE-821/2 blocked ATR pathway activation and released the cells from the G2/M block caused by UVA and PUVA, but did not affect apoptosis caused by other chemotherapeutics (etoposide, gemcitabine, doxorubicine) or by hydrogen peroxide. Knockdown of ATR and Chk1 with siRNA also blocked the ATR pathway and released the cells from G2/M block but did not sensitize the cells to UVA as observed with the small molecule inhibitors. The latter suggested that the synergism between VE-821/2 or Chir-124 and UVA was not solely caused by specific blocking of ATR kinase but also ATR-independent photosensitization. This hypothesis was further verified by administrating VE-821/2 or Chir-124 before and after UVA irradiation, as well as comparing their activity with other ATR and Chk1 inhibitors (AZD6738 and MK8776). We found that only VE-821/2 and Chir-124 kinase inhibitors had synergistic effect with UVA, and only if applied before treatment with UVA. CONCLUSION: Small molecule ATR and Chk1 inhibitors potently sensitize lymphoma cells to UVA radiation and induce a prominent apoptotic response. Interestingly, this effect is due to the dual (kinase inhibiting and photosensitizing) mode of action of these compounds.

Patient Adherence to Biologic Agents in Psoriasis.

BACKGROUND: Low adherence to therapies in psoriasis decreases treatment outcomes and increases the total health care costs. In spite of the wide use of biologic agents, patients' adherence to these drugs has not been extensively investigated. OBJECTIVE: The aim of this study is to measure adherence to the biologic drugs in a population of patients treated for psoriasis vulgaris using the medication possession ratio (MPR) index and to survey patients' attitudes to the treatment. METHODS: This is a single-center study on 247 patients with psoriasis vulgaris treated with adalimumab (n = 113), etanercept (n = 39), and ustekinumab (n = 95). MPR calculation was calculated monthly based on the hospital records documenting the dispensing of biologics to the patients. Clinical data [Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), presence of psoriatic arthritis, concomitant treatment, and cause for treatment discontinuation] were obtained from the national database DERMBIO. Patients' attitudes and beliefs were measured using the Medication Adherence Rating Scale (MARS). RESULTS: A total of 93.5% of all patients had an MPR ≥0.8, indicating very good adherence. MPR was independent of patients' age, gender, median PASI or DLQI score, concomitant diagnosis of psoriatic arthritis, or treatment with methotrexate. MPR for etanercept was slightly lower than that for ustekinumab and adalimumab. The MARS questionnaire documented satisfactory understanding of the treatment and its adverse effects, and positive attitudes to the treatment. CONCLUSION: Adherence to biologic therapies is very high in patients with psoriasis, which is consistent with a positive attitude to the treatment.

STAT3/5-Dependent IL9 Overexpression Contributes to Neoplastic Cell Survival in Mycosis Fungoides.

PURPOSE: Sustained inflammation is a key feature of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). Resident IL9-producing T cells have been found in skin infections and certain inflammatory skin diseases, but their role in MF is currently unknown. EXPERIMENTAL DESIGN: We analyzed lesional skin from patients with MF for the expression of IL9 and its regulators. To determine which cells were producing IL9, high-throughput sequencing was used to identify malignant clones and Vb-specific antibodies were employed to visualize malignant cells in histologic preparations. To explore the mechanism of IL9 secretion, we knocked down STAT3/5 and IRF4 by siRNA transfection in CTCL cell lines receiving psoralen+UVA (PUVA) ± anti-IL9 antibody. To further examine the role of IL9 in tumor development, the EL-4 T-cell lymphoma model was used in C57BL/6 mice. RESULTS: Malignant and reactive T cells produce IL9 in lesional skin. Expression of the Th9 transcription factor IRF4 in malignant cells was heterogeneous, whereas reactive T cells expressed it uniformly. PUVA or UVB phototherapy diminished the frequencies of IL9- and IL9r-positive cells, as well as STAT3/5a and IRF4 expression in lesional skin. IL9 production was regulated by STAT3/5 and silencing of STAT5 or blockade of IL9 with neutralizing antibodies potentiated cell death after PUVA treatment in vitro IL9-depleted mice exhibited a reduction of tumor growth, higher frequencies of regulatory T cells, and activated CD4 and CD8 T lymphocytes. CONCLUSIONS: Our results suggest that IL9 and its regulators are promising new targets for therapy development in mycosis fungoides. Clin Cancer Res; 22(13); 3328-39. ©2016 AACR.

Triterpenoid α-amyrin stimulates proliferation of human keratinocytes but does not protect them against UVB damage.

Rhaponticum carthamoides plants ("maral root") are widely used in Siberian folk medicine. The present study reports for the first time the presence of pentacyclic terpenoid, α-amyrin, in methanol extract from leaves of this plant. α-Amyrin induced proliferation of human keratinocytes (HaCaT) by about 18% while other extract components were ineffective. A panel of biochemical and cell-based assays testing the antioxidative and cytoprotective activites of α-amyrin indicated no antioxidative activity of this compound. α-Amyrin did not protect HaCaT cells against the damage caused by UVB radiation.