This paper is in the following e-collection/theme issue:

Non-Randomized Study Protocols and Methods (Non-eHealth) (540) Precision Medicine (63) Clinical Cancer Research (71) Skin Cancer and Melanoma Prevention (109)

Published on in Vol 13 (2024)

Preprints (earlier versions) of this paper are available at https://preprints.jmir.org/preprint/55723, first published .
Predictive and Prognostic Biomarkers in Patients With Mycosis Fungoides and Sézary Syndrome (BIO-MUSE): Protocol for a Translational Study

Predictive and Prognostic Biomarkers in Patients With Mycosis Fungoides and Sézary Syndrome (BIO-MUSE): Protocol for a Translational Study

Predictive and Prognostic Biomarkers in Patients With Mycosis Fungoides and Sézary Syndrome (BIO-MUSE): Protocol for a Translational Study

Authors of this article:

Emma Belfrage1 Author Orcid Image ;   Sara Ek2 Author Orcid Image ;   Åsa Johansson3 Author Orcid Image ;   Hanna Brauner4, 5 Author Orcid Image ;   Andreas Sonesson1 Author Orcid Image ;   Kristina Drott6 Author Orcid Image
Article Authors Cited by Tweetations (2) Metrics

    Protocol

    1Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Skåne University Hospital, Lund, Sweden

    2Department of Immunotechnology, Faculty of Engineering, Lund University, Lund, Sweden

    3Clinical Genetics and Pathology, Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Skåne University Hospital, Lund, Sweden

    4Division of Dermatology and Venereology, Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

    5Department of Dermatology and Venereology, Karolinska University Hospital, Stockholm, Sweden

    6Department of Hematology and Transfusion Medicine, Skåne University Hospital, Lund, Sweden

    Corresponding Author:

    Emma Belfrage, MD

    Division of Dermatology and Venereology, Department of Clinical Sciences

    Lund University

    Skåne University Hospital

    Lasarettsgatan 15

    Lund, 222 41

    Sweden

    Phone: 46 707367293

    Email: emma.belfrage@med.lu.se


    Background: Cutaneous T-cell lymphoma (CTCL) is a rare group of lymphomas that primarily affects the skin. Mycosis fungoides (MF) is the most common form of CTCL and Sézary syndrome (SS) is more infrequent. Early stages (IA-IIA) have a favorable prognosis, while advanced stages (IIB-IVB) have a worse prognosis. Around 25% of patients with early stages of the disease will progress to advanced stages. Malignant skin-infiltrating T-cells in CTCL are accompanied by infiltrates of nonmalignant T-cells and other immune cells that produce cytokines that modulate the inflammation. Skin infection, often with Staphylococcus aureus, is frequent in advanced stages and can lead to sepsis and death. S. aureus has also been reported to contribute to the progression of the disease. Previous reports indicate a shift from Th1 to Th2 cytokine production and dysfunction of the skin barrier in CTCL. Treatment response is highly variable and often unpredictable, and there is a need for new predictive and prognostic biomarkers.

    Objective: This prospective translational study aims to identify prognostic biomarkers in the blood and skin of patients with MF and SS.

    Methods: The Predictive and Prognostic Biomarkers in Patients With MF and SS (BIO-MUSE) study aims to recruit 120 adult patients with MF or SS and a control group of 20 healthy volunteers. The treatments will be given according to clinical routine. The sampling of each patient will be performed every 3 months for 3 years. The blood samples will be analyzed for lactate dehydrogenase, immunoglobulin E, interleukins, thymus and activation-regulated chemokine, and lymphocyte subpopulations. The lymphoma microenvironment will be investigated through digital spatial profiling and single-cell RNA sequencing. Microbiological sampling and analysis of skin barrier function will be performed. The life quality parameters will be evaluated. The results will be evaluated by the stage of the disease.

    Results: Patient inclusion started in 2021 and is still ongoing in 2023, with 18 patients and 20 healthy controls enrolled. The publication of selected translational findings before the publication of the main results of the trial is accepted.

    Conclusions: This study aims to investigate blood and skin with a focus on immune cells and the microbiological environment to identify potential new prognostic biomarkers in MF and SS.

    Trial Registration: ClinicalTrials.gov NCT04904146; https://www.clinicaltrials.gov/study/NCT04904146

    International Registered Report Identifier (IRRID): DERR1-10.2196/55723

    JMIR Res Protoc 2024;13:e55723

    doi:10.2196/55723

    Keywords

    mycosis fungoides; Sézary syndrome; prognostic; predictive; protocol; translational study; cutaneous T-cell lymphomas (CTCL); skin microbiota; immunology; tissue microenvironment; epigenetics; quality of life; skin infection; Staphylococcus aureus; progression of disease; skin barrier; prognostic biomarkers; adult; adults; elderly; spatial; microbiological sampling; blood; study protocol 


    Mycosis Fungoides and Sézary Syndrome

    Cutaneous T-cell lymphoma (CTCL) is a rare group of lymphomas that primarily affects the skin [1-3]. The pathogenesis of CTCL is not yet fully understood [3]. The annual incidence of CTCL is 0.7 per 100,000. Mycosis fungoides (MF) is the most prevalent form and comprises 60% of CTCL, with a higher male incidence (1.6:1.0) and a peak age incidence between 50 and 74 years [4]. Since MF often has a chronic course, its prevalence is considerably higher. The skin lesions in MF can be patches, plaques, tumors, or erythroderma. Sézary syndrome (SS) is an aggressive leukemic variant of the disease and constitutes only 5% of CTCL; it is defined as a triad of erythroderma, lymphadenopathy, and the presence of neoplastic T-cells in peripheral blood [5]. The extent of the disease in the skin is measured according to the Modified Severity-Weighted Assessment Tool [6,7]. Both MF and SS are staged according to the same tumor-node-metastasis-blood (TNMB) classification, assessing the involvement of skin, peripheral lymph nodes, peripheral blood, and visceral organs [8].

    Prognosis of MF and SS

    The TNMB stage at diagnosis remains the most important prognostic factor [9,10]. Many patients with early stages of MF have an indolent disease with a 5-year disease-specific survival of 89% to 98% [8,11]. However, approximately 25% of patients with early stages of disease will later progress to advanced stages [4]. Patients with advanced stages of MF have a 5-year disease-specific survival of 18% to 56% associated with treatment failure [8,10]. The 5-year disease-specific survival of SS is 36% [3,8,10].

    Multivariate analyses of cohorts of patients with MF and SS have identified potential adverse prognostic factors in the early stages of disease consisting of male gender, aged >60 years, plaques, folliculotropic disease, and stage N1/NX and negative prognostic factors for advanced disease consisting of male gender, aged >60 years, stages B1/B2 and N2/N3, and visceral involvement [12,13]. The presence of plaque lesions in the early stage of the disease, large cell transformation in the skin, and elevated lactate dehydrogenase are also identified as adverse prognostic factors [11,14,15]. Still, there is an unmet clinical need to identify which patients will progress to an advanced stage of disease, and there is a great need for new reliable prognostic markers.

    Treatments for MF and SS

    The therapeutic options for MF and SS range from skin-directed therapy (SDT) to systemic treatment, and the selection of appropriate treatment is primarily based on the stage of the disease. There are only a few randomized controlled trials for the treatment of MF and SS, and current recommendations for treatment are mainly based on consensus meetings and international guidelines [4,5,10]. The treatment of the early stages of MF aims at modulating the immune response in the skin through SDT, such as topical corticosteroids and UV light therapy. Local radiation therapy usually has a good effect in all stages. In early stages that are refractory to SDT or in advanced stages, systemic treatment is used, including retinoid derivatives, low-dose methotrexate, and interferon alfa. In patients with lymphoma cells expressing CD30, targeted chemotherapy with brentuximab vedotin can be used. Further, standard chemotherapy such as gemcitabine or doxorubicin can be used; however, this often results in only short remission periods. Extracorporeal photopheresis can be used in erythrodermic stages of MF and SS and mogamulizumab and alemtuzumab can be used in advanced stages of disease. Highly selected patients with advanced stages of disease can be considered for allogeneic stem cell transplantation. Histone deacetylase (HDAC) inhibitors such as vorinostat and romidepsin are approved by the US Food and Drug Administration but are not commonly used in Europe [16,17]. Total skin electron beam therapy can be used in widespread disease in the skin or before allogeneic stem cell transplantation. Treatment response is unpredictable, and there is an unmet clinical need to find reliable predictive markers.

    Immunological Changes of the Microenvironment of CTCL in Skin and Blood

    Early stages of CTCL derive from mature CD4+ T-cells, or rarely CD8+ T-cells, in the skin. The restriction to the skin suggests that the affected cells are dependent on the specific cutaneous microenvironment, including cytokines and adhesion molecules. Malignant skin-infiltrating cells are accompanied by infiltrates of nonmalignant T-cells and other immune cells. The infiltrating benign immune cells produce a variety of cytokines that modulate cutaneous inflammation and are important constituents of the local environment of the tumor, fostering proliferation, survival, and migration [3]. Attempts to associate a unique cytokine profile of the disease based on skin or blood samples have indicated that a shift from Th1 to Th2 cytokine production accompanies disease progression [18,19], but the mechanisms behind this shift are not completely known [20]. In the advanced stages of the disease, a reduction of skin-infiltrating CD8+ T-cells has been observed, as well as a shift toward M2 polarized macrophages and increased frequencies of NK cells and B-cells [21,22]. Other major immunological changes also facilitate the environment of the lymphoma cells and impair the host immunological defense [22]. The hypothesis of this study is to further explore these immunological changes through analysis of lymphocyte subpopulations in blood and skin together with cytokine expression in plasma through protein array analysis. We also hypothesize that we will detect other cells, molecules, and factors in the microenvironment of the tumor that could influence the clinical course of CTCL.

    Epigenetic Modifications in CTCL

    Regulation of DNA transcription is complex, and the mechanisms of regulation of DNA transcription in CTCL are partially unknown. HDACs can regulate the expression of genes and activities of transcription factors involved in malignant transformation and immune defense. HDACs act mainly through alteration of the structural components of chromatin by histone deacetylation, thus affecting the 3D conformation of DNA without changing or interrupting its sequence. Epigenetic drugs such as HDAC inhibitors have shown promising results in patients with advanced disease, emphasizing the impact of epigenetic regulators on the disease. Based on phase II data demonstrating long-term remission in 35% of heavily pretreated patients, HDAC inhibitors have been approved by the US Food and Drug Administration for second-line treatment of CTCL [16,17]. Although the dysregulated function of HDAC inhibitors may have an important role in malignant transformation and in the response to cancer treatment, the in vivo mechanisms behind the effects of HDAC inhibitors in CTCL are largely unknown. However, next-generation sequencing data have shown amino-acid or copy number alterations of 13 chromatin modifiers in 1% to 7% of CTCL cases, respectively, suggesting a mutation-driven epigenetic imbalance in CTCL [23]. Interestingly, HDAC inhibitors have been shown to reprogram the epigenome of host nonmalignant T-cells toward normal patterns, emphasizing the role of the host T-cells for therapy response [24,25].

    Microbiological Changes and Skin Barrier Function in MF and SS

    Skin infections, often with Staphylococcus aureus, are frequently seen in advanced stages of MF and SS. In patients who are immunocompromised, skin infections can lead to sepsis and death. Some studies indicate that a shift from Th1 to Th2 cytokine production and dysfunction of the skin barrier contribute to skin infections [26,27]. The underlying basis for the microbiological changes and the skin barrier function in CTCL need to be further elucidated for their potential role in the pathogenesis and progression.

    Goals of This Study

    The primary objective of this study is to identify serum-protein markers for 6-month progression-free survival (PFS) and to identify the immune cell profile in blood for 6-month PFS.

    Secondary objectives are to identify the immune cell profile in the skin for 6-month PFS, analyze the lymphoma microenvironment in the skin for 6-month PFS, identify the skin barrier and skin microbiology profiles for 6-months PFS, and identify the epigenetic changes in lymphoma T-cells and host T-cells for 3 months PFS.


    Study Design

    The Predictive and Prognostic Biomarkers in Patients With MF and SS (BIO-MUSE) study is a translational prospective study, aiming to include 120 adult patients with MF and SS and a control group of 20 healthy volunteers (Figure 1). Sampling of each patient will be performed every 3 months for 3 years. The control group will be examined on 3 different occasions at least 2 months apart. This study is presently open at Skåne University Hospital and aims to open at Karolinska University Hospital. The multicenter study design enables other Swedish sites to be included, after further ethical approval.

    ‎
    Figure 1. Study design of the BIO-MUSE study. BIO-MUSE: Predictive and Prognostic Biomarkers in Patients With Mycosis Fungoides and Sézary Syndrome; CT: computed tomography; DLQI: Dermatology Life Quality Index; IgE: immunoglobulin E; IL-6: interleukin-6; IL-8: interleukin-8; IL-10: interleukin-10; IL-1beta: interleukin-1beta; LDH: lactate dehydrogenase; MF: mycosis fungoides; mSWAT: Modified Severity-Weighted Assessment Tool; NRS: Numerical Rating Scale; sIL-2R: soluble interleukin-2 receptor; SS: Sézary syndrome; TARC: thymus and activation-regulated chemokine; TEWL: transepidermal water loss; TNMB: tumor-node-metastasis-blood.

    Ethical Considerations

    This study’s protocol is written per the Declaration of Helsinki and the International Council for Harmonisation’s good clinical practice guidelines. This study was registered with ClinicalTrials.gov (NCT04904146) and approved by the Swedish Ethics Committee (2019-05130). Written informed consent will be obtained from participants according to the Declaration of Helsinki and International Council for Harmonisation’s good clinical practice guidelines.

    Eligibility Criteria

    Inclusion criteria will be patients aged 18-100 years with histologically confirmed MF and SS (stage IA-IVB) and World Health Organization performance status 0-3. The inclusion criteria for the healthy control group will be healthy adults aged 18-100 years with World Health Organization performance status 0-2 and the absence of any malignant, autoimmune, or infectious disease. The exclusion criteria for both groups are psychiatric illnesses or conditions that could interfere with the ability to understand the requirements of this study.

    Stage of Disease and Modified Severity-Weighted Assessment Tool

    Patients will be staged according to the TNMB classification [8]. The extent of disease in the skin will be measured according to the Modified Severity-Weighted Assessment Tool [6,7]. Progression or regression will be defined as a shift from one stage to another.

    Treatment of MF and SS

    The treatments will be given according to clinical routine and national and international guidelines for MF and SS and participation in this study will not affect the choice of treatments. Ongoing treatments will be documented.

    Blood Samples for Soluble Interleukin-2 Receptor, Interleukins, and Thymus and Activation-Regulated Chemokine/CCL17

    Blood samples in patients will be analyzed for complete blood count, liver and kidney function, lactate dehydrogenase, soluble interleukin-2 receptor, interleukin-6, interleukin-8, interleukin-10, and thymus and activation-regulated chemokine/CCL17 (Multimedia Appendix 1).

    Blood Samples for Analysis of Immunoglobulin E Against Specific Antigen

    Total immunoglobulin E and specific immunoglobulin E for S. aureus enterotoxin A (m80), enterotoxin B (m81), toxic shock syndrome toxin-1 (Rm226), Malassezia (m227), and Candida albicans (m5) will be analyzed in patients and in the control group (Multimedia Appendices 1 and 2, respectively).

    Blood Samples for Analysis of Lymphocyte Subpopulations

    Flow cytometry of peripheral blood will be performed in patients to analyze the T-cell subpopulations including naive, effector, and memory T-cells (including Th1, Th2, and Th17 cells) and activated and regulatory T-cells. Monoclonal antibodies recognizing CD4, CD8, CD197, CD45RA, CD25, CD194, CD127, CD45RO, CD183, and CD196 will be used [28]. In addition, to evaluate the presence of clonal T-cells in peripheral blood and biopsies the following panel: T-cell receptor fluorescein isothiocyanate, TRBC1 phycoerythrin, CD16 electron coupled dye, CD2 PC7, CD3 BV421, CD4PC5.5, CD7 A700, CD8 KrO, CD26 allophycocyanine, and CD45 allophycocyanine-H7 will be used [29] (Multimedia Appendices 1 and 3, respectively).

    Serum-Based Profiling of Immune-Related Soluble Proteins

    Broad sets of serum-based protein profiling focused on immune-related proteins will be performed in patients. Global protein profiling will be performed using commercially available methods, allowing high-plex analyses of immune-related soluble molecules. State-of-the-art bioinformatic tools will be applied for preprocessing and analysis of data (Multimedia Appendix 1).

    Assessment of Tumor Microenvironment by Digital Spatial Profiling and Single-Cell RNA Sequencing

    To allow the study of the cellular tumor immune microenvironment, 2 biopsies from affected skin and 1 biopsy from unaffected skin, at least 5 cm away from affected skin, will be taken. In the control group, 1 skin biopsy is taken from the upper arm. The skin biopsies will be formalin-fixed and paraffin-embedded. In addition, blood will be drawn from patients and healthy controls and peripheral blood mononuclear cells will be cryopreserved.

    Multiplex analyses of samples taken before and after progression have the potential to contribute to novel biological knowledge as previously discussed in a recent review by the group Kalliara et al [30] and will be performed in samples collected over time. In brief, in skin biopsies, Digital Spatial Profiling will be performed to study immune infiltration in CTCL and how it evolves during the progression of the disease [31]. Single-cell RNA and T-cell receptor sequencing will be applied to sorted CD3+ cells to follow the evolution of the malignant clone over time. Moreover, additional assessments of genetic and epigenetic changes in the tumor and tumor microenvironment will be performed in skin biopsies (Multimedia Appendix 1).

    Assessment of Epigenetic Factors in Circulating Tumor Cells Compared to Normal and Host T-Cells

    Cell sorting of CD3+ cells from peripheral blood in patients with blood involvement will be performed using FACSAria (BD, Bioscience). When possible, 2-3 million cells will be sorted from each patient to allow the preparation of DNA for epigenetic analysis and RNA for gene expression analysis. Analysis of histone modifications and chromatin accessibility will be performed by ChIP-seq (chromatin immunoprecipitation with sequencing) and ATAC-seq (assay of transposase-accessible chromatin with sequencing), respectively. Moreover, molecular profiling using nCounter analysis (NanoString Technologies, Inc) will be performed to profile cells through expression panels focused on immune profiling and proliferative signaling pathways (Multimedia Appendix 1).

    Microbiological Sampling

    Microbiological samples will be analyzed from affected skin and from unaffected skin 5 cm away from affected skin, preferably from the upper body, and from nares in patients. In the control group, the microbiological samples will be analyzed from the upper arm and from the nares (Multimedia Appendices 1 and 2, respectively).

    Analysis of Skin Barrier Function

    Skin barrier function will be measured as transepidermal water loss (TEWL) with a closed chamber TEWL meter, VapoMeter 300 (Delfin Technologies Ltd), according to guidelines [32]. TEWL will be measured on affected skin and on unaffected skin 5 cm away from affected skin, preferably from the upper body. TEWL will be measured on the upper arm in the control group (Multimedia Appendices 1 and 2).

    Hematopathology of Skin, Lymph Node, Bone Marrow, and Tumor Biopsies

    Hematopathology of skin biopsy will be performed in affected skin from patients and is optional from lymph nodes, bone marrow, and tumors (Multimedia Appendices 1 and 3).

    Patient-Oriented Life Quality Measures

    Patient-oriented life quality measures will be performed. The Dermatology Life Quality Index [33], Peak Pruritus Numerical Rating Scale [34], Sleep Numerical Rating Scale, and Connor-Davidson Resilience Scale [35] will be used (Multimedia Appendix 1).

    Statistical Analysis

    The sample profiles from patients with an early stage of disease (stage IA-IIA) will be compared to samples from patients with an advanced stage of disease (stage IIB-IVB) using multivariate analysis with principal component analysis. Individual samples will be compared between the groups using the Mann-Whitney U test. Other translational samples will be presented by descriptive statistics. Progression-free and overall survival will be presented using Kaplan-Meier plots.


    Patient inclusion started in 2021 and is still ongoing in December 2023, with 18 patients and 20 healthy controls enrolled. Until December 2023, a total of 2 included patients have declined further participation due to the extra visits in this study. Further, 2 patients have died from MF during this study. The publication of selected translational findings before the publication of the main results of the trial is accepted, and data analysis is in progress.

    The evaluation of the stage of the disease will be observed every 3 months according to the TNMB classification, where the shift from one stage to another implies progression or treatment response. After the study, patients will be grouped as either early stage of the disease (IA-IIA) or advanced stage of the disease (IIB-IVB). The patients crossing over from the early stage of the disease to the advanced stage of the disease group will be analyzed both individually and as a group. Approximately 30% (36/120) of patients are estimated to be in the advanced stage of the disease group. The translational samples in the early stage of the disease group will be compared to samples from the advanced stage of the disease group. The treatments directed against MF are documented throughout this study. Excluded patients will be presented along with the final results. Depending on patient numbers, treatment data will be presented descriptively, or if possible, to support data on treatment predictive biomarkers.


    Principal Findings

    This study aims to find potential predictive and prognostic biomarkers in patients with MF and SS. This study will investigate translational samples from skin and blood concerning the stage of the disease over time, which has the advantage of monitoring patients with consecutive samplings to be able to capture changes before and during a possible progression. This study will be able to compare differences in patients with early (IA-IIA) and advanced (IIB-IVB) stages of the disease. It will also be possible to analyze the data separately for patients with MF and SS, respectively. The translational samplings in this study are chosen to be able to detect changes in the immune system and in tumor cells, as well as changes in the skin barrier function and the skin microbiota. There is a clinically unmet need to find new predictive and prognostic biomarkers in MF and SS, and studies further exploring these areas are therefore a high priority. The research team, techniques, and management presented in this protocol have capacities to investigate new aspects and bring new knowledge to the field of CTCL. This study combines a multidisciplinary outpatient clinic with extensive translational research sampling, which has considerable potential to lead to true patient benefit.

    Limitations

    MF and SS are rare diseases, and the inclusion of the proposed number of patients in this study protocol may take considerable time. To reach the estimated number of patients in this study, inclusion will also start at Karolinska University Hospital, and to expand this study further, cooperations with other centers is ongoing. Another possible limitation is that the control group will be followed for a shorter period compared to the patients.

    Comparison With Prior Work

    The Prospective Cutaneous Lymphoma International Prognostic Index study is an ongoing international study of a confirmed early-stage MF cohort, which is being followed up to identify prognostic factors in the hope of providing better management and improving survival by identifying patients at risk of disease progression [36].

    Conclusions

    The BIO-MUSE study is a prospective translational study aiming to identify new prognostic and predictive biomarkers in blood and skin in patients with MF and SS.

    Acknowledgments

    We thank Anna Porwit, professor emerita, Department of Pathology, Lund University, Skåne University Hospital, Lund, Sweden, for help with planning the hematopathology analysis. We are grateful to Andreas Lennartsson, Department of Biosciences and Nutrition, Karolinska Institutet, Sweden for help with planning the epigenetic analysis. This study was funded by the Stiftelsen Siv-Inger och Per-Erik Anderssons Minnesfond (FBKS-2019-14-(210)), Berta Kamprad foundation (S19 0238), Swedish Cancer Society, Swedish Society for Medical Research (S17-0104), the Swedish Cancer Foundation (190408Fk; 232960), Region Stockholm (clinical research appointment [ref20190859] and ALF medicine [RS2020-0731]), HudFonden (3281), Clas Groschinsky (M19390), Magnus Bergvall (2019-03538), Radiumhemmet (211032), and Karolinska Institutet foundations (2018-02203). The funders had no role in this study’s design, data collection and analysis, interpretation of results, paper preparations, or decision to submit the report for publication.

    Data Availability

    The data sets analyzed during this study are available from corresponding authors upon reasonable request.

    Authors' Contributions

    KD is the principal investigator of this study. EB and KD are responsible for including patients at Skåne University Hospital, Lund Sweden. HB is responsible for including patients at Karolinska University Hospital, Stockholm. AS is responsible for the microbiological translational part of this study. SE and ÅJ are responsible for the immunology translational part of this study. EB, AS, and KD were the major contributors to writing this paper. All the authors participated in the design of this study and read, commented upon, and approved this final paper.

    Conflicts of Interest

    EB has received lecturing fees from Novartis. AS has received lecturing and consulting fees from Sanofi, Pfizer, AbbVie, and LEO Pharma. KD has received honoraria from Kyowa Kirin, Roche, and Incyte, and is a shareholder and board member of Respiratorius AB. HB has received honoraria for serving on an advisory board from Kyowa Kirin and a lecturing fee from Janssen-Cilag.

    Multimedia Appendix 1

    Translational samples and logistics for patients in the Predictive and Prognostic Biomarkers in Patients With Mycosis Fungoides and Sézary Syndrome (BIO-MUSE) study.

    DOCX File , 22 KB
    Multimedia Appendix 2

    Translational samples and logistics for the healthy control group in the Predictive and Prognostic Biomarkers in Patients With Mycosis Fungoides and Sézary Syndrome (BIO-MUSE) study.

    DOCX File , 16 KB
    Multimedia Appendix 3

    Planned assessments of hematopathology in the skin, lymph node, bone marrow, and tumor biopsies.

    DOCX File , 17 KB
    1. Willemze R, Cerroni L, Kempf W, Berti E, Facchetti F, Swerdlow SH, et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood. 2019;133(16):1703-1714. [FREE Full text] [CrossRef] [Medline]
    2. Alaggio R, Amador C, Anagnostopoulos I, Attygalle AD, Araujo IB, Berti E, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia. 2022;36(7):1720-1748. [FREE Full text] [CrossRef] [Medline]
    3. Dummer R, Vermeer MH, Scarisbrick JJ, Kim YH, Stonesifer C, Tensen CP, et al. Cutaneous T cell lymphoma. Nat Rev Dis Primers. 2021;7(1):61. [FREE Full text] [CrossRef] [Medline]
    4. Gilson D, Whittaker SJ, Child FJ, Scarisbrick JJ, Illidge TM, Parry EJ, et al. British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of primary cutaneous lymphomas 2018. Br J Dermatol. 2019;180(3):496-526. [FREE Full text] [CrossRef] [Medline]
    5. Willemze R, Hodak E, Zinzani PL, Specht L, Ladetto M, ESMO Guidelines Committee. Primary cutaneous lymphomas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv30-iv40. [FREE Full text] [CrossRef] [Medline]
    6. Stevens SR, Ke MS, Parry EJ, Mark J, Cooper KD. Quantifying skin disease burden in mycosis fungoides-type cutaneous T-cell lymphomas: the Severity-Weighted Assessment Tool (SWAT). Arch Dermatol. 2002;138(1):42-48. [FREE Full text] [CrossRef] [Medline]
    7. Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al. Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol. 2011;29(18):2598-2607. [FREE Full text] [CrossRef] [Medline]
    8. Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007;110(6):1713-1722. [FREE Full text] [CrossRef] [Medline]
    9. Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol. 2003;139(7):857-866. [FREE Full text] [CrossRef] [Medline]
    10. Latzka J, Assaf C, Bagot M, Cozzio A, Dummer R, Guenova E, et al. EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - update 2023. Eur J Cancer. 2023;195:113343. [FREE Full text] [CrossRef] [Medline]
    11. Agar NS, Wedgeworth E, Crichton S, Mitchell TJ, Cox M, Ferreira S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of cancer staging proposal. J Clin Oncol. 2010;28(31):4730-4739. [FREE Full text] [CrossRef] [Medline]
    12. Benton EC, Crichton S, Talpur R, Agar NS, Fields PA, Wedgeworth E, et al. A Cutaneous Lymphoma International Prognostic Index (CLIPi) for mycosis fungoides and Sezary syndrome. Eur J Cancer. 2013;49(13):2859-2868. [FREE Full text] [CrossRef] [Medline]
    13. Amorim GM, Corbellini JPN, Quintella DC, Cuzzi T, Ramos-E-Silva M. Evaluation of the Cutaneous Lymphoma International Prognostic Index in patients with early stage mycosis fungoides. An Bras Dermatol. 2018;93(5):680-685. [FREE Full text] [CrossRef] [Medline]
    14. Scarisbrick JJ, Prince HM, Vermeer MH, Quaglino P, Horwitz S, Porcu P, et al. Cutaneous lymphoma international consortium study of outcome in advanced stages of mycosis fungoides and sézary syndrome: effect of specific prognostic markers on survival and development of a prognostic model. J Clin Oncol. 2015;33(32):3766-3773. [FREE Full text] [CrossRef] [Medline]
    15. Zackheim HS, Amin S, Kashani-Sabet M, McMillan A. Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients. J Am Acad Dermatol. 1999;40(3):418-425. [FREE Full text] [CrossRef] [Medline]
    16. Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J, Allen SL, et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 2011;117(22):5827-5834. [FREE Full text] [CrossRef] [Medline]
    17. Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012;30(6):631-636. [FREE Full text] [CrossRef] [Medline]
    18. Vowels BR, Cassin M, Vonderheid EC, Rook AH. Aberrant cytokine production by Sezary syndrome patients: cytokine secretion pattern resembles murine Th2 cells. J Invest Dermatol. 1992;99(1):90-94. [FREE Full text] [CrossRef] [Medline]
    19. Brunner PM, Jonak C, Knobler R. Recent advances in understanding and managing cutaneous T-cell lymphomas. F1000Res. 2020;9:F1000. [FREE Full text] [CrossRef] [Medline]
    20. Guenova E, Watanabe R, Teague JE, Desimone JA, Jiang Y, Dowlatshahi M, et al. TH2 cytokines from malignant cells suppress TH1 responses and enforce a global TH2 bias in leukemic cutaneous T-cell lymphoma. Clin Cancer Res. 2013;19(14):3755-3763. [FREE Full text] [CrossRef] [Medline]
    21. Nielsen PR, Eriksen JO, Wehkamp U, Lindahl LM, Gniadecki R, Fogh H, et al. Clinical and histological characteristics of mycosis fungoides and Sézary syndrome: a retrospective, single-centre study of 43 patients from Eastern Denmark. Acta Derm Venereol. 2019;99(13):1231-1236. [FREE Full text] [CrossRef] [Medline]
    22. Scheffschick A, Nenonen J, Xiang M, Winther AH, Ehrström M, Wahren-Herlenius M, et al. Skin infiltrating NK cells in cutaneous T-cell lymphoma are increased in number and display phenotypic alterations partially driven by the tumor. Front Immunol. 2023;14:1168684. [FREE Full text] [CrossRef] [Medline]
    23. Park J, Yang J, Wenzel AT, Ramachandran A, Lee WJ, Daniels JC, et al. Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p.Q575E). Blood. 2017;130(12):1430-1440. [FREE Full text] [CrossRef] [Medline]
    24. Qu K, Zaba LC, Satpathy AT, Giresi PG, Li R, Jin Y, et al. Chromatin accessibility landscape of cutaneous T cell lymphoma and dynamic response to HDAC inhibitors. Cancer Cell. 2017;32(1):27-41.e4. [FREE Full text] [CrossRef] [Medline]
    25. Cao K, Wang G, Li W, Zhang L, Wang R, Huang Y, et al. Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity. Oncogene. 2015;34(49):5960-5970. [FREE Full text] [CrossRef] [Medline]
    26. Suga H, Sugaya M, Miyagaki T, Ohmatsu H, Kawaguchi M, Takahashi N, et al. Skin barrier dysfunction and low antimicrobial peptide expression in cutaneous T-cell lymphoma. Clin Cancer Res. 2014;20(16):4339-4348. [FREE Full text] [CrossRef] [Medline]
    27. Mirvish JJ, Pomerantz RG, Falo LD, Geskin LJ. Role of infectious agents in cutaneous T-cell lymphoma: facts and controversies. Clin Dermatol. 2013;31(4):423-431. [FREE Full text] [CrossRef] [Medline]
    28. Maecker HT, McCoy JP, Nussenblatt R. Standardizing immunophenotyping for the Human Immunology Project. Nat Rev Immunol. 2012;12(3):191-200. [FREE Full text] [CrossRef] [Medline]
    29. Novikov ND, Griffin GK, Dudley G, Drew M, Rojas-Rudilla V, Lindeman NI, et al. Utility of a simple and robust flow cytometry assay for rapid clonality testing in mature peripheral t-cell lymphomas. Am J Clin Pathol. 2019;151(5):494-503. [FREE Full text] [CrossRef] [Medline]
    30. Kalliara E, Belfrage E, Gullberg U, Drott K, Ek S. Spatially guided and single cell tools to map the microenvironment in cutaneous t-cell lymphoma. Cancers (Basel). 2023;15(8):2362. [FREE Full text] [CrossRef] [Medline]
    31. Merritt CR, Ong GT, Church SE, Barker K, Danaher P, Geiss G, et al. Multiplex digital spatial profiling of proteins and RNA in fixed tissue. Nat Biotechnol. 2020;38(5):586-599. [CrossRef]
    32. Pinnagoda J, Tupker RA, Agner T, Serup J. Guidelines for Transepidermal Water Loss (TEWL) measurement. A report from the standardization group of the European Society of Contact Dermatitis. Contact Dermatitis. 1990;22(3):164-178. [FREE Full text] [CrossRef] [Medline]
    33. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-216. [FREE Full text] [CrossRef] [Medline]
    34. Ständer S, Augustin M, Reich A, Blome C, Ebata T, Phan N, et al. Pruritus assessment in clinical trials: consensus recommendations from the International Forum for the Study of Itch (IFSI) special interest group scoring itch in clinical trials. Acta Derm Venereol. 2013;93(5):509-514. [FREE Full text] [CrossRef] [Medline]
    35. Connor KM, Davidson JRT. Development of a new resilience scale: the Connor-Davidson Resilience Scale (CD-RISC). Depress Anxiety. 2003;18(2):76-82. [FREE Full text] [CrossRef] [Medline]
    36. Scarisbrick JJ, Quaglino P, Prince HM, Papadavid E, Hodak E, Bagot M, et al. The PROCLIPI international registry of early-stage mycosis fungoides identifies substantial diagnostic delay in most patients. Br J Dermatol. 2019;181(2):350-357. [FREE Full text] [CrossRef] [Medline]

    ‎
    ATAC-seq: assay of transposase-accessible chromatin with sequencing
    BIO-MUSE: Predictive and Prognostic Biomarkers in Patients With Mycosis Fungoides and Sézary Syndrome
    CBC: complete blood count
    ChIP-seq: chromatin immunoprecipitation with sequencing
    CTCL: cutaneous T-cell lymphoma
    HDAC: histone deacetylase
    MF: mycosis fungoides
    PFS: progression-free survival
    SDT: skin-directed therapy
    SS: Sézary syndrome
    TEWL: transepidermal water loss
    TNMB: tumor-node-metastasis-blood

    Edited by A Mavragani; submitted 21.12.23; peer-reviewed by D Kumar, K Zhang; comments to author 05.02.24; revised version received 08.02.24; accepted 09.02.24; published 04.04.24.

    Copyright

    ©Emma Belfrage, Sara Ek, Åsa Johansson, Hanna Brauner, Andreas Sonesson, Kristina Drott. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 04.04.2024.

    This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on https://www.researchprotocols.org, as well as this copyright and license information must be included.