Management Of Cutaneous T-cell Lymphoma Research Articles

Fine-Tuning Low-Dose Total Skin Electron Therapy for Optimal Management of Cutaneous T-Cell Lymphoma: A Comparative Analysis of Regimens

BackgroundLow-dose total skin electron beam therapy (TSEBT) is a proven treatment for managing cutaneous T-cell lymphoma (CTCL) and Sezary syndrome with skin burden. We performed a retrospective comparison of response rates and time to progression for patients receiving low-dose TSEBT based on dose per fractionation, total dose, and stage. MethodsOne hundred and ten patients with CTCL and Sezary syndrome were treated with 135 courses of low-dose (400-1500 cGy) TSEBT or STSEBT (subtotal skin electron therapy) at multiple centers of a single institution between 8/2003 and 6/2023. Patients were stratified according to total dose, dose per fraction, and stage. ResultsThe median follow-up was 301 days [IQR 141, 767]. The median age at treatment was 69.9 years (range 29.7 – 96.5). T-stage distribution was as follows: 3 (2.7%) T1, 74 (67.3%) T2, 16 (14.5%) T3, and 17 (15.5%) T4. AJCC 8th edition Stage distribution was as follows: 3 (2.7%) IA, 53 (48.2%) IB, 3 (2.7%) IIA, 16 (14.5%) IIB, 8 (7.3%) IIIA, 19 (17.3%) IVA, 8 (7.3%) IVB. There was no significant difference in disease distribution between patients treated with different fractionation schemes. The overall response rate was 89.6%. Forty-four courses (32.6%), 34 courses (25.2%), and 43 (31.9%) resulted in a complete, near-complete, and partial response, respectively. Fourteen courses (10.4%) resulted in no clinical response. For all patients, the median time to response was 43.0 days (IQR 23.0 – 70). The median time to skin progression for all patients was 107.5 days [IQR 67.8 – 233.5]. ConclusionsThis analysis demonstrated that CTCL patients treated with low-dose RT delivered over various fractionation schemes had similar overall response rates and median time to progression.

BI17 A novel multidisciplinary clinic for the management of cutaneous T-cell lymphoma

Abstract Mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL) is a rare condition that can present diagnostic difficulty and challenging management as no standard pathway exists. Patients require haematology and dermatology involvement to ensure optimal management, and the British Association of Dermatologists guidelines suggest regional supranetwork skin MDT for the majority of patients. However, this distances patients and local clinicians from the decision-making process. We propose a multidisciplinary model that includes local dermatology and haematology teams with the assistance of a regional expert to evaluate all of a region’s patients with MF-CTCL to ensure appropriate staging and management. On review of our cohort of patients with MF-CTCL, there were 42 patients with only 50% staged. We proposed a day-long multidisciplinary clinic model that enabled all patients with MF-CTCL to attend the dermatology department to receive a teaching session by trained nurses, a 30-minute consultation with a dermatology consultant with direct access to a specialist haematology consultant and a regional cutaneous lymphoma specialist, and access to on-the-day blood tests and diagnostic biopsies if needed. Twenty-six patients attended the clinic; 22 were confirmed to have MF-CTCL, 21 of whom were appropriately staged on the day. Ninety-five per cent of patients said they felt ‘extremely involved and informed’ about their management and treatment decisions after the clinic (vs. 19% preclinic). Ninety-five per cent would recommend the clinic to a family or friend, and 90% would attend a similar clinic in the future. From a clinician perspective, the survey responses showed high value in having repeated exposure to patients with CTCL, understanding the management options for MF-CTCL, face-to-face discussions with the multidisciplinary team (MDT) and longer clinic appointments. In conclusion, we offer this MDT clinic model as an efficient means for delivering patient-centred management and care, continuing education to local referring clinicians and ensuring close working relationships between dermatology and haematology. We propose running this clinic annually to ensure that all patients with MF-CTCL have appropriate investigation, staging and management pathways. The success of the clinic has led the department to adopt this model in other areas such as inflammatory conditions.

Extracorporeal Photopheresis Suppresses Transplant Fibrosis by Inducing Decorin Expression in Alveolar Macrophages.

Extracorporeal Photopheresis Suppresses Transplant Fibrosis by Inducing Decorin Expression in Alveolar Macrophages.

Development of liposomal topical gel of bexarotene for effective management of cutaneous t-cell lymphoma: Formulation to preclinical assessment

Development of liposomal topical gel of bexarotene for effective management of cutaneous t-cell lymphoma: Formulation to preclinical assessment

The optimal use of chlormethine gel for mycosis fungoides: An expert consensus from Germany, Austria and Switzerland (DACH region).

In Europe chlormethine gel is licensed for the management of patients with mycosis fungoides of all stages. However, the optimal regimen regarding frequency and dosing as well as combination and maintenance therapy is not well established. Ten experts experienced in research and management of cutaneous T-cell lymphomas from Germany, Austria, and Switzerland (DACH region) were asked in written form to report on indication for chlormethine gel, frequency of use, monitoring, concomitant therapies, adverse effects, combination therapies in later stages of the disease, maintenance therapy, and adherence to this therapy for mycosis fungoides. The structured answers were discussed in a consensus conference and recommendations were developed. Essential for therapy with chlormethine gel is an individualized and symptom-oriented management. Because of the lack of systemic resorption of topically administered chlormethine gel, systemic adverse events are unlikely. An allergic or irritative-toxic contact dermatitis is common but manageable with adaptation of the regimen, interruption of administration, and symptom-specific supportive measurements. A step-up initial approach with application of chlormethine gel every other day is associated with a better tolerability, especially if it is alternated with topical corticosteroids. The use of chlormethine gel in the management of mycosis fungoides is often limited by a concomitant contact dermatitis. An adequate therapeutic regimen and the management of adverse effects can preclude an unnecessary withdrawal of therapy so that more patients can benefit from this treatment option.

Cutaneous T-cell lymphoma: diagnosing subtypes and the challenges.

Cutaneous T-cell lymphoma is a rare type of extranodal non-Hodgkin's lymphoma that primarily affects the skin. The uncertain pathogenesis and variable clinical presentation make the diagnosis and management of cutaneous T-cell lymphoma a challenge. Cutaneous T-cell lymphoma is a chronic, relapsing illness with treatment aimed at symptomatic relief and improving patient related quality of life. Early-stage cutaneous T-cell lymphoma typically follows an indolent course, often being mistaken for benign dermatological conditions which can lead to a diagnostic delay. Advanced stage cutaneous T-cell lymphoma has a poor prognosis with significant morbidity. Accurate diagnosis and early involvement of a specialist team is paramount to ensure correct management and improved patient outcomes. Promising advances are being made to develop novel agents which could improve prognosis and quality of life. This article provides an overview of the two main subtypes of cutaneous T-cell lymphoma: mycosis fungoides and Sézary syndrome. Clinical presentation, histopathological correlation and diagnostic challenges are reviewed alongside example case studies.

Contemporary Treatment Patterns and Response in Relapsed/Refractory Cutaneous T-Cell Lymphoma (CTCL) across Five European Countries.

Simple SummaryRecent studies have mostly focused on the treatment of advanced mycosis fungoides and Sézary syndrome and less on the treatment of relapsed or refractory (R/R) cases of cutaneous T-cell lymphoma (CTCL). There is also a paucity of data on the treatment and outcomes of primary cutaneous anaplastic large cell lymphoma and other rare CTCL subtypes. This European observational study provided real-world data on the current treatments used in the management of CTCL across three lines of therapy. As a result, there was a significant level of heterogeneity in treatment types than expected by European guidelines. These findings highlight the lack of consensus in relapsed CTCL, as well as the urgent unmet treatment needs.The treatment pattern of cutaneous T-cell lymphoma (CTCL) remains diverse and patient-tailored. The objective of this study was to describe the treatment patterns and outcomes in CTCL patients who were refractory or had relapsed (R/R) after a systemic therapy. A retrospective chart review study was conducted at 27 sites in France, Germany, Italy, Spain and the United Kingdom (UK) of patients who received a first course of systemic therapy and relapsed or were refractory. Data were collected longitudinally from diagnosis to first-, second- and third-line therapy. The study included 157 patients, with a median follow-up of 3.2 years. In total, 151 proceeded to second-line and 90 to third-line therapy. In the first line (n = 147), patients were treated with diverse therapies, including single- and multi-agent chemotherapy in 67 (46%), retinoids in 39 (27%), interferon in 31 (21%), ECP in 4 (3%), corticosteroids in 3 (2%) and new biological agents in 3 (2%). In the second line, the use of chemotherapy and retinoids remained similar to the first line, while the use of new biologics increased slightly. In sharp contrast to the first line, combination chemotherapy was extremely diverse. In the third line, the use of chemotherapy remained high and diverse as in the second line. From the time of first R/R, the median PFS was 1.2 years and the median OS was 11.5 years. The presented real-world data on the current treatments used in the management of R/R CTCL in Europe demonstrate the significant heterogeneity of systemic therapies and combination therapies, as expected from the European guidelines.

PLCγ1/PKCθ Downstream Signaling Controls Cutaneous T-Cell Lymphoma Development and Progression

Developing mechanistic rationales can improve the clinical management of cutaneous T-cell lymphomas. There is considerable genetic and biological evidence of a malignant network of signaling mechanisms, highly influenced by deregulated TCR/PLCγ1 activity, controlling the biology of these lesions. In addition, activated signal transducer and activator of transcription 3 is associated with clinical progression, although the alterations responsible for this have not been fully elucidated. Here, we studied PLCγ1-dependent mechanisms that can mediate STAT3 activation and control tumor growth and progression. Downstream of PLCγ1, the pharmacological inhibition and genetic knockdown of protein kinase C theta (PKCθ) inhibited signal transducer and activator of transcription 3 activation, impaired proliferation, and promoted apoptosis in cutaneous T-cell lymphoma cells. A PKCθ-dependent transcriptome in mycosis fungoides/Sézary syndrome cells revealed potential effector genes controlling cytokine signaling, TP53, and actin cytoskeleton dynamics. Consistently, an invivo chicken embryo model xenografted with mycosis fungoides cells showed that PKCθ blockage abrogates tumor growth and spread to distant organs. Finally, the expression of a number of PKCθ target genes found in mycosis fungoides cells significantly correlated with that of PRKCQ (PKCθ) in 81 human mycosis fungoides samples. In summary, PKCθ can play a central role in the activation of malignant cutaneous T-cell lymphoma mechanisms via multiple routes, including, but not restricted to, STAT3. These mechanisms may, in turn, serve as targets for specific therapies.

Bio-P-09 - Combination of ruxolitinib with resminostat exerts antitumor effects in a chick embryo metastasis model

Bio-P-09 - Combination of ruxolitinib with resminostat exerts antitumor effects in a chick embryo metastasis model

Bio-O1-08 - PLCγ1/PKCθ and its downstream effectors in cutaneous T-cell lymphoma development and progression

Developing mechanistic rationales can improve the clinical management of cutaneous T-cell lymphomas (CTCL). In the last few years, the use of Next Generation Sequencing (NGS) approaches has revealed a rich landscape of genomic alterations potentially influencing the biology of these entities. In this regard, multiple genetic and biological evidences point at a malignant network of signaling mechanisms, highly influenced by deregulated TCR/PLCγ1 activity, to control the biology of CTCLs. In addition, activated STAT3 is associated with clinical progression, although the specific mechanisms responsible for this have not been fully elucidated. Here we studied PLCγ1-dependent mechanisms that can activate JAK/STAT and control tumor growth and progression. Downstream of PLCγ1, we identified PKCθ (a specific T cell PKC isoform) to mediate JAK/STAT3 activation and control CTCL cell proliferation and viability. In vivo, PKCθ blockage in CTCL cells, impaired tumor development and cells spreading to the liver and the lungs. In light of these results, we sought to identify specific PKCθ downstream effectors, that in addition to JAK/STATs, could help understanding its biological role in CTCL. To this end, we studied PKCθ-dependent transcriptome as well as its protein interactome in CTCL cells. This approach helped detecting a number of hits that can potentially explain STAT3 phosphorylation in CTCL cells (i.e. RACK1), and highlight a number of oncogenic activities controlled by PKCq, like mitochondrial activity (i.e. ASK1, HSPA9) and cytoskeletal regulation (i.e. ARHGAP-19 or CCT4, 5). As a result, this dual approach helped identifying a number of protein effectors and target genes that can participate in important CTCL activities like for example cytokine signaling, mitochondrial activity, TP53, and actin cytoskeleton dynamics. Finally, we took advantage of Nanostring to study the expression of a selection of PKCθ target genes, in a cohort of 81 human MF samples and control inflammatory dermatoses. In this context, PRKCQ (PKCθ) gene expression was significantly upregulated in MF cases vs. controls. Moreover, the expression of target genes like PRKACB (encoding for PKA isoform B) or the lymphocyte specific actin binding LCP1 and LCP1, positively correlated with that of PRKCQ expression in MF cases. On the other hand, genes like FGFR3 and RHOB showed a significant yet inverse correlation with PRKCQ in robust agreement with the data generated in CTCL cells. Overall, the results show a PKCθ gene signature that is significant and differentially expressed amongst different MF cases, at different stages of the disease. Moreover, this signature highlights novel CTCL disease mechanisms with translational potential in diagnosis and targeted therapy. In summary, we have uncover a series of PKCθ-dependent effectors/routes that can play a central role in the biology of CTCLs and help to develop novel approaches to diagnose and treat these malignancies.

Cutaneous T-cell lymphoma: practical recommendations to enhance clinical practice.

Management of cutaneous T-cell lymphoma should provide a holistic approach to a patient's wellbeing. Treatments depend on the stage of lymphoma. Patients with the early stages tend to have a near-normal life expectancy. Management should be aimed at improving the extent of disease and reducing symptoms with minimal therapeutic adverse effects. Skin-directed treatments are preferred and may be used in combination with treatments for symptom relief such as anti-pruritic medication. In advanced stages of disease where the median life expectancy is reduced the aims are also to prevent disease progression and prolong life, and this requires a multidisciplinary approach. Symptom control remains important as patients often have painful, itchy disfiguring lesions which greatly impact on health-related quality of life. National and international guidelines provide stage-related treatment options to be considered with first-line options followed by subsequent second-line therapies. All are listed in no particular order of preference and are chosen according to patients' needs and expertise of the treating centre. Several first-line options may be chosen before moving to the second-line options. Three drugs received European Medicines Agency approval in 2017 and 2018 (chlormethine gel, brentuximab and mogamulizumab) but there still remains an unmet need for more improved treatments or combinations. Most treatments only result in a partial response and there is no cure for early-stage disease; as such, patients live for a long time with their disease. In the advanced stages if a good response is achieved eligible patients will be considered for an allogeneic haematopoietic stem cell transplant.

Critical concepts and management recommendations for cutaneous T-cell lymphoma: A consensus-based position paper from the Italian Group of Cutaneous Lymphoma.

In this paper, we present a review of critical concepts, and produce recommendations on management issues in cutaneous T-cell lymphomas (CTCLs) of adults. A panel of nine experts was selected for their expertise in research and clinical practice of CTCLs. During an initial meeting, the areas of major concern in the management of CTCLs were selected by generating and rank-ordering clinical key questions using the criterion of clinical relevance, through group discussion. Recommendations were achieved by multiple-step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. The panel produced recommendations on how to facilitate the clinical suspicion of CTCL; indication of cutaneous biopsy; optimal histological diagnosis, immunohistochemistry and genetic markers; and staging pathway and up-to-date therapeutics (with particular focus on new treatments). The critical concept of integration of the different medical expertise in the management of the patients with CTCL was thoroughly examined. These recommendations are intended for use not only by expert centers but above all by "not experienced" dermatologists and hematologists as well as general practitioners.

The Novel Role of Antibiotic Treatment in the Management of Cutaneous T-Cell Lymphoma (CTCL) Patients

The Novel Role of Antibiotic Treatment in the Management of Cutaneous T-Cell Lymphoma (CTCL) Patients

160 Mechanisms governing promoter methylation and apoptosis in cutaneous T-cell lymphoma: implications for therapy with methotrexate and JAK-inhibitors

Cutaneous T-cell lymphoma (CTCL) is characterized by resistance to apoptosis involving dysregulation of the FAS ligand (FASL) - FAS death receptor pathway. CTCL cells also exhibit constitutively activated STAT proteins, which are known to upregulate and bind DNA methyltransferases (DNMTs). We hypothesized that, like many other tumor suppressor genes, FAS and FASL expression is at least partially regulated by promoter methylation. Earlier, we showed that methotrexate (MTX), a known folate antagonist, acts as a DNA methylation inhibitor via depleting the methyl donor, S-adenosylmethionine (SAM), in CTCL cells. Pyrosequencing analysis of FAS and FASL promoters showed that MTX inhibited methylation of certain CpG sites in these genes, which resulted in increased FAS/FASL expression and subsequent apoptosis via activated caspase 8. We found that shRNA mediated genetic knockdown of DNMT -1 and -3A also resulted in upregulation of FASL mRNA and protein in CTCL cell lines. However, the reduction in FASL promoter methylation induced by MTX was generally superior to that induced by shRNA knockdown and was not improved by a combination of MTX plus knockdown. Because STAT proteins help regulate DNMTs, we also evaluated the effect of multiple JAK inhibitors (fedratinib, tofacitinib, and ruxolitinib) in CTCL cells and Sezary patient’s blood. Among these, fedratinib treatment was most effective in decreasing viability, spheroid formation, and inducing apoptosis. These responses were accompanied by decreased phosphorylation of STAT3 at tyrosine-705. Taken together, our data demonstrate that enhanced apoptosis of CTCL can be induced by MTX, DNMT knockdown and JAK inhibitors. This is consistent with a mechanistic cascade in which activated STATs enhance DNMT activities that in turn suppress the expression of apoptotic factors and promote CTCL survival. Our findings suggest a therapeutic role for MTX and JAK inhibitors in the management of CTCL.

Gene expression analysis in Cutaneous T-Cell Lymphomas (CTCL) highlights disease heterogeneity and potential diagnostic and prognostic indicators

ABSTRACTCutaneous T-Cell Lymphomas (CTCL) are rare, but potentially devastating malignancies, whose pathogenesis remains poorly elucidated. Unfortunately, currently it is not possible to predict based on the available criteria in which patients the cancer will progress and which patients will experience an indolent disease course. Furthermore, at early stages this malignancy often masquerades as psoriasis, chronic eczema or other benign inflammatory dermatoses. As a result, it takes on average 6 y to diagnose this lymphoma since its initial presentation. In this study, we performed transcription expression profiling using TruSeq targeted RNA gene expression on 181 fresh and formalin-fixed and paraffin-embedded (FFPE) skin samples from CTCL patients and patients affected by benign inflammatory dermatoses that often mimic CTCL clinically and on histology (e.g., psoriasis, chronic eczema, etc.) We also analyzed multiple longitudinal biopsies that were obtained from the same patients over time. Our results underscore significant molecular heterogeneity with respect to gene expression between different patients and even within the same patients over time. Our study also confirmed TOX, FYB, LEF1, CCR4, ITK, EED, POU2AF, IL26, STAT5, BLK, GTSF1 and PSORS1C2 genes as being differentially expressed between CTCL and benign skin biopsies. In addition, we found that differential expression for a subset of these markers (e.g., TOX, FYB, GTSF1 and CCR4) may be useful in prognosticating this disease. This research, combined with other molecular analyses, prepares the foundation for the development of personalized molecular approach toward diagnosis and management of CTCL.

Experimental treatment strategies in primary cutaneous T-cell lymphomas.

Cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of malignancies derived from skin-homing or resident T cells. Effective treatments are limited, thus new therapies are in development to address the unmet medical need. Recent studies uncovering the genetic alteration in cutaneous T-cell lymphoma have enhanced our understanding of the importance of the T-cell activation/survival pathways, dysregulated immune system, and the relevance of chromatin modification in the pathogenesis of CTCL. New advances in cancer immunomodulation such as with PD1/PD-L1 inhibitors and novel targeted antitumor therapies such as brentuximab vedotin and mogamulizumab as well as potential combination strategies are promising for improving clinical efficacy with manageable toxicity profile. All these new therapeutic approaches have resulted in broadening the treatment landscape and a potential paradigm shift in the management of CTCL.

The Use of Transcriptional Profiling to Improve Personalized Diagnosis and Management of Cutaneous T-cell Lymphoma (CTCL).

Although many patients with mycosis fungoides presenting with stage I disease enjoy an indolent disease course and normal life expectancy, about 15% to 20% of them progress to higher stages and most ultimately succumb to their disease. Currently, it is not possible to predict which patients will progress and which patients will have a stable disease. Previously, we conducted microarray analyses with RT-PCR validation of gene expression in biopsy specimens from 60 patients with stage I-IV cutaneous T-cell lymphoma (CTCL), identified three distinct clusters based upon transcription profile, and correlated our molecular findings with 6 years of clinical follow-up. We test by RT-PCR within our prediction model the expression of about 240 genes that were previously reported to play an important role in CTCL carcinogenesis. We further extend the clinical follow-up of our patients to 11 years. We compare the expression of selected genes between mycosis fungoides/Sézary syndrome and benign inflammatory dermatoses that often mimic this cancer. Our findings demonstrate that 52 of the about 240 genes can be classified into cluster 1-3 expression patterns and such expression is consistent with their suggested biologic roles. Moreover, we determined that 17 genes (CCL18, CCL26, FYB, T3JAM, MMP12, LEF1, LCK, ITK, GNLY, IL2RA, IL26, IL22, CCR4, GTSF1, SYCP1, STAT5A, and TOX) are able to both identify patients who are at risk of progression and also distinguish mycosis fungoides/Sézary syndrome from benign mimickers. This study, combined with other gene expression analyses, prepares the foundation for the development of personalized molecular approach toward diagnosis and treatment of CTCL.

Modification of extracorporeal photopheresis technology with porphyrin precursors. Comparison between 8-methoxypsoralen and hexaminolevulinate in killing human T-cell lymphoma cell lines in vitro

BackgroundExtracorporeal photopheresis that exposes isolated white blood cells to 8-methoxypsoralen (8-MOP) and ultraviolet-A (UV-A) light is used for the management of cutaneous T-cell lymphoma and graft-versus-host disease. 8-MOP binds to DNA of both tumor and normal cells, thus increasing the risk of carcinogenesis of normal cells; and also kills both tumor and normal cells with no selectivity after UV-A irradiation. Hexaminolevulinate (HAL)-induced protoporphyrin-IX is a potent photosensitizer that localizes at membranous structures outside of the nucleus of a cell. HAL-mediated photodynamic therapy selectively destroys activated/transformed lymphocytes and induces systemic anti-tumor immunity. The aim of the present study was to explore the possibility of using HAL instead of 8-MOP to kill cells after UV-A exposure. MethodsHuman T-cell lymphoma Jurkat and Karpas 299 cell lines were used to evaluate cell photoinactivation after 8-MOP and/or HAL plus UV-A light with cell proliferation and long term survival assays. The mode of cell death was also analyzed by fluorescence microscopy. ResultsCell proliferation was decreased by HAL/UV-A, 8-MOP/UV-A or HAL/8-MOP/UV-A. At sufficient doses, the cells were killed by all the regimens; however, the mode of cell death was dependent on the treatment conditions. 8-MOP/UV-A produced apoptotic death exclusively; whereas both apoptosis and necrosis were induced by HAL/UV-A. Conclusion8-MOP can be replaced by HAL to inactivate the Jurkat and Karpas 299 T-cell lymphoma cells after UV-A irradiation via apoptosis and necrosis. This finding may have an impact on improved efficacy of photopheresis.

Histone Deacetylase Inhibitors

Histone deacetylase inhibitors (HDAC-Is) are agents that have demonstrated anticancer activity in vivo and in vitro, leading to clinical trials evaluating their efficacy in multiple cancer types. Only two HDAC-Is are currently approved by the U.S. Food and Drug Administration, vorinostat and romidepsin, both with indications for cutaneous T-cell lymphoma. Romidepsin has an additional approval in peripheral T-cell lymphoma. Promising clinical trial results in other cancer types will likely lead to expanded use of these and other HDAC-Is. To provide care for patients receiving these agents, oncology nurses should be knowledgeable about the emerging role of HDAC-Is. This article reviews the mechanism of action of HDAC-Is, currently approved therapies, and nursing management of cutaneous T-cell lymphoma.

Management of cutaneous T-cell lymphoma

#### Key Points Cutaneous T-cell lymphoma (CTCL) is an uncommon cutaneous malignancy that usually presents with patches and/or plaques, less commonly with tumours and/or haematological involvement Mycosis fungoides is usually an indolent condition that can be managed with skin-directed therapies