Skin-directed Therapies Research Articles

Tumor RNA Sequencing Identifies a Group of Patients with Mycosis Fungoides with Failure of Skin-Directed Therapies

Tumor RNA Sequencing Identifies a Group of Patients with Mycosis Fungoides with Failure of Skin-Directed Therapies

Maintenance therapy for CTCL: importance for prevention of disease progression

There are no established maintenance protocols for cutaneous lymphomas. We aim to determine patient treatments and outcomes during the COVID-19 pandemic in order to uncover the most effective maintenance protocols for cutaneous lymphomas and impact of treatment interruption. Data was collected retrospectively from nine international institutions, including 149 patients. Younger patients had earlier stages of disease and were most frequently treated with skin-directed therapies including topical steroids, mechlorethamine gel, and phototherapy. Treatment interruption varied by treatment type and stage, with patients on topical therapies and earlier stages of disease being least likely to experience interruption. Treatment interruption was significantly associated with progression of disease and worse outcomes, with twice as many patients progressing who had interruption compared to those without interruption. This study may demonstrate the significance of continuous maintenance therapies, even in younger patients with early stages of disease.

Predictors for the use of systemic therapy in stage IB Mycosis fungoides.

The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is aprospective analysis of an international database. Here we examine front-line treatments and quality of life (QoL) inpatients with newly diagnosed mycosis fungoides (MF). To identify (i) differences in first-line approaches according to tumour-nodes-metastasis-blood (TNMB)staging; (ii) parameters related to a first-line systemic approach and (iii) response rates and QoL measures. In total, 395 newly diagnosed patients with early-stage MF (stage IA-IIA) were recruited from 41 centresin 17 countries between 1 January 2015 and 31 December 2018 following central clinicopathological review. The most common first-line therapy was skin-directed therapy (SDT) (322 cases, 81·5%), while a smallerpercentage (44 cases, 11·1%) received systemic therapy. Expectant observation was used in 7·3%. In univariateanalysis, the use of systemic therapy was significantly associated with higher clinical stage (IA, 6%; IB, 14%; IIA,20%; IA-IB vs. IIA, P < 0·001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0·001), higher modified Severity Weighted Assessment Tool (> 10, 15%; ≤ 10, 7%; P = 0·01) and folliculotropic MF (FMF) (24% vs. 12%, P = 0·001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs.T1a/T2a, odds ratio 3·07) and FMF (odds ratio 2·83). The overall response rate (ORR) to first-line SDT was 73%,while the ORR to first-line systemic treatments was lower (57%) (P = 0·027). Health-related QoL improvedsignificantly both in patients with responsive disease and in those with stable disease. Disease characteristics such as presence of plaques and FMF influence physician treatment choices,and SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, futuretreatment guidelines for early-stage MF need to address these issues.

Skin-directed therapy and biologic response modifiers in mycosis fungoides.

The most common and widespread type of cutaneous T-cell lymphoma is mycosis fungoides (MF), and it has a multiphasic clinical and biological course, with early stages being indolent for many years and later stages being faster and more aggressive. The clinical stage has a significant impact on the management and course of treatment: in the early stages, skin-directed therapies (SDT) plus/or biologic response modifiers (BRM); in the later stages, radiotherapy and/or systemic therapies. Even though national and international societies and groups periodically update their clinical recommendations, there is still no universally accepted approach. This paper reviews and discusses the various SDT and BRM options, either separately or in combination.

Radiation therapy in mycosis fungoides.

Radiation therapy (RT) is administered with varying intentions, sometimes even several times in the same or in different body areas, to over 50% of patients with neoplastic conditions. Numerous techniques are available to patients in the clinical evolution of mycosis fungoides (MF), and there are several indications for radiation therapy (RT). RT as a skin-directed therapy is very widely used in these patients, either alone or in conjunction with other therapies. The application of RT, a tried-and-true therapy that improves MF patients' quality of life and treatment, can be encouraged by a multidisciplinary approach and an understanding of current methods and action mechanisms.

Systemic treatments with monoclonal antibodies in mycosis fungoides and Sézary syndrome.

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most prevalent non-Hodgkin lymphomas that comprise cutaneous T-cell lymphomas (CTCL), accounting for more than 70% of cases. Following the Tumor Lymph nodes Metastasis Blood system, disease staging is carried out, and within ten years, about thirty percent of patients in the early stages will have advanced disease. Plaques, folliculotropism, and age over 60 are risk factors for progression. A 5-year survival rate of less than 20% is associated with LCT in MF. Treatment requires an interdisciplinary approach; skin-directed therapies are available for early stages of the disease, but there are no curative options for advanced stages of the disease other than allogeneic stem cell transplantation. Because of their severe symptoms and poor treatment efficacy, patients in advanced stages have a lower quality of life and a lower chance of survival. In patients with CD30-expressing CTCL, Brentuximab Vedotin has demonstrated better response rates and progression-free survival (PFS); in advanced SS, mogamulizumab has significantly increased PFS. These findings emphasize the need to standardize prognostic factors and improve CTCL treatment.

New Genetic Markers of Skin T-Cell Lymphoma Treatment.

Cutaneous T-cell lymphomas (CTCL) can be described as chronic skin inflammation lesions with the content of malignant T cells and they are considered to be T-cell-mediated skin diseases. CD147 is recognized as a 58-kDa cell surface glycoprotein of the immunoglobulin superfamily; it can induce the synthesis of MMPs (matrix metalloproteinases) on the surface of tumor cells where it was originally identified. It can also function in adjacent tumor fibroblasts using CD147-CD147 interactions. The polymorphism rs8259 T/A is situated in the untranslated region (3'UTR) of the CD147 gene. HLA DRB1*1501 takes part in the process of presentation and recognition of different antigens to T cells. It can be expressed by antigen-presenting cells-macrophages, dendritic cells, and B cells. The aim of the study is to test genotype-phenotype associations of both polymorphisms including therapy in a large cohort of CTCL patients. A final total of 104 CTCL patients were enrolled in the study. For the first remission at the clinic department, they were treated by means of local skin-directed therapy, phototherapy, and systemic therapy. Genomic DNA was isolated from peripheral blood leukocytes. A standard technique using proteinase K was applied. The polymorphisms rs8259 T/A (CD147 gene) and rs3135388 (HLA DRB1*1501) were detected through standard PCR-restriction fragment length polymorphism methods. The severity of the disease (patients with parapsoriasis, stages IA and IB, vs patients with stages IIB, IIIA, and IIIB) was associated with the CD147 genotype: the AA variant was 3.38 times more frequent in more severe cases, which reflects the decision on systemic therapy (p = 0.02, specificity 0.965). The AA genotype in the CD147 polymorphism was 12 times more frequent in patients who underwent systemic therapy of CTCL compared to those not treated with this therapy (p = 0.009, specificity 0.976). The same genotype was also associated with radiotherapy-it was observed 14 times more frequently in patients treated with radiotherapy (p = 0.009, specificity 0.959). In patients treated with interferon α therapy, the AA genotype was observed to be 5.85 times more frequent compared to the patients not treated with interferon therapy (p = 0.03, specificity 0.963). The HLA DRB1*1501 polymorphism was associated with local skin-directed therapy of CTCL. The CC genotype of the polymorphism was observed to be 3.57 times more frequent in patients treated with local therapy (p = 0.008, specificity 0.948). When both polymorphisms had been calculated together, even better results were obtained: the AACC double genotype was 11 times more frequent in patients with severe CTCL (p = 0.009, specificity 0.977). The TACT double genotype was associated with local skin-directed therapy (0.09 times lower frequency, p = 0.007, sensitivity 0.982). The AACC genotype was 8.9 times more frequent in patients treated by means of systemic therapy (p = 0.02, specificity 0.976) and as many as 18.8 times more frequent in patients treated with radiotherapy (p = 0.005, specificity 0.969). Thus, the AACC double genotype of CD147 and DRB1*1501 polymorphisms seems to be a clinically highly specific marker of severity, systemic therapy and radiotherapy of patients with T-cell lymphoma. Although genotyping results were not known during the treatment decision and could not modify it, the clinical decision on severity and therapy reflected some aspects of the genetic background of this complicated T-cell-associated disease very well.

Perspectives on Psoriasiform Adverse Events from Immune Checkpoint Inhibitors: Lessons Learned from Our Practice.

Background: New oncologic therapies, including immune checkpoint inhibitors (ICIs), have revolutionized the survival and prognosis of cancer patients. However, these therapies are often complicated by immune-related adverse effects (irAEs) that may impact quality of life and potentially limit their use. Among these adverse events are psoriasis and psoriatic arthritis that may develop de novo or flare under treatment with ICIs. Given the exceptional immune status of patients receiving ICIs, managing these conditions without interfering with the effect of the oncologic treatment may prove very challenging. Aim: To review the literature data on ICI-induced psoriasis exacerbation or development, to present our own experience, and to discuss the pathogenic mechanisms underlying this association and the optimal therapeutic approach for these patients. Case Reports: We report three cases of ICI-induced de novo psoriasis and two cases of ICI-induced psoriasis exacerbation that required systemic treatment. Oral acitretin treatment successfully controlled psoriasis lesions in three cases and allowed for the continuation of immunotherapy. Literature Review: We performed a medical literature search across several databases (PubMed, Medline, Google Scholar) using the search terms "immune checkpoint inhibitor-induced psoriasis/psoriasiform dermatitis/psoriasis arthritis". We identified and revised 80 relevant publications that reported 1102 patients with psoriasis and/or psoriasis arthritis induced or exacerbated by ICIs. We assessed the type of cancer, the therapeutic agent involved, the clinical form of psoriasis, the presence or absence of psoriatic arthritis, the personal and family history of psoriasis, the age, the gender, the time until onset or exacerbation of skin lesions, the specific treatment recommended, the need for ICI discontinuation, and the patient's outcome. Conclusions: As ICIs represent a fairly novel therapy, the association with several adverse effects is only now unraveling. Psoriasis exacerbation or onset following the initiation of immunotherapy is one such example, as more and more reports and case series are being published. Awareness of the relationship between psoriasis and treatment with ICIs, prompt recognition, and initiation of adequate skin-directed therapies are essential for the avoidance of skin lesions worsening, the need for systemic treatments that may interfere with ICIs' effects, or the discontinuation of the latter. In the absence of generally accepted guidelines, it is advisable to treat patients with severe, widespread psoriasis with drugs that do not impair the effects of immunotherapy and thus do not alter the patient's prognosis.

Multi-center retrospective review of vitiligo-like lesions in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors.

Cutaneous adverse effects from cyclin-dependent 4 and 6 kinase inhibitors (CDK4/6i) used in metastatic breast cancer are prevalent and well described. Vitiligo-like lesions have been reported and are rare. They can negatively impact patients' quality of life and may be associated with survival benefits. We describe the clinical characteristics of vitiligo-like lesions in an international cohort of patients treated with CDK4/6i to help improve recognition and management. Retrospective review of patients diagnosed with vitiligo-like lesions from CDK4/6i from five academic institutions in the USA and Europe was performed. Ten patients were included in the study. Median age of our patients was 55 (range 37-86). Median progression-free survival was 24months in 5 patients. The median time to rash was 10months. Sun-exposed areas such as the arms and face were the most affected areas. Multiple skin-directed therapies such as topicals, laser, and phototherapy were trialed with minor success. Mild repigmentation was seen in one patient treated with ruxolitinib cream. CDK4/6 treatment was discontinued due to the vitiligo-like lesions in one patient. Clinical characteristics are similar to previously reported findings in case reports and series. We add topical ruxolitinib as a potential treatment option for these patients and include data regarding progression-free survival that should continue to be collected. No definitive conclusions can be made regarding survival benefits from our cohort. Clinicians should refer these patients to dermatologists to aid with management.

Chlormethine gel in combination with other therapies for treatment of mycosis fungoides: a review with patient cases.

Topical chlormethine gel has been approved as monotherapy for treatment of adult patients with mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma. In clinical practice, chlormethine gel is often combined with other skin-directed or systemic therapies to optimize response and target recalcitrant lesions. Positive outcomes with combination regimens using chlormethine gel and topical corticosteroids, phototherapy, retinoids, methotrexate, or interferon-α have been reported in literature. However, there are no treatment guidelines on the use of combination regimens with chlormethine gel. To provide real-world evidence and guidance on the use of chlormethine gel combination regimens, several cases of patients treated with chlormethine gel combined with phototherapy (n = 5), retinoids (n = 16), or mogamulizumab (n = 3) are presented. These different combination regimens showed promising results. Most patients had a complete or partial response following treatment and the combinations were well-tolerated over extended treatment periods. Patients receiving chlormethine gel with retinoids had long-term periods of remission, even after treatment discontinuation. Durations of response of up to 3 years were observed in these patients. This long-term disease control may be the result of disease-modifying effects of chlormethine. Previous studies have shown targeted reductions in malignant T-cell clones in patients treated with chlormethine gel as well as improved post-treatment responses. Further research is needed to determine the effectiveness and safety of combination treatment regimens with chlormethine gel and to assess the impact chlormethine gel has on disease control.

Gut microbiota analyses of cutaneous T-cell lymphoma patients undergoing narrowband ultraviolet B therapy reveal alterations associated with disease treatment.

Recent studies have shown a close relationship between cutaneous T-cell lymphoma (CTCL) and its microbiome. CTCL disease progression is associated with gut dysbiosis and alterations in bacterial taxa parallel those observed in immunologically similar atopic dermatitis. Moreover, the microbial profile of lesional skin may predict response to narrowband ultraviolet B (nbUVB), a common skin-directed therapy. However, the relationship between the gut microbiome, an immunologically vital niche, and nbUVB remains unexplored in CTCL. Herein, we performed 16S rRNA sequencing and PICRUSt2 predictive metagenomics on DNA extracted from stool swabs of 13 CTCL patients treated with nbUVB, 8 non-treated patients, and 13 healthy controls. Disease response was assessed with modified Severity Weighted Assessment Tool (mSWAT); of nbUVB-treated patients, 6 improved (decreased mSWAT), 2 remained stable, and 5 worsened (increased mSWAT). Protective commensal bacteria including Lactobacillaceae and Erysipelatoclostridiaceae were significantly less abundant in CTCL patients compared to controls. With treatment, the CTCL gut microbiome exhibited decreased phylogenetic diversity and lower relative abundance of pro-inflammatory Sutterellaceae. Sutterellaceae was also significantly more abundant in patients who worsened, and Eggerthellaceae and Erysipelotrichaceae trended higher in patients who improved. Finally, PICRUSt2 functional predictions based on shifts in abundance of bacterial sequences repeatedly identified alterations in inositol degradation, which plays a key role in host immunomodulation, including inositol phospholipid signaling relevant to T-cell survival and proliferation. Our results bolster the paradigm of gut dysbiosis in CTCL and its functional implications in disease pathogenesis, and further delineate bacterial taxa associated with nbUVB response and with nbUVB treatment itself.

Dynamic Changes in Lymph Node Size and Skin Scoring Predict Response to Treatment in CTCL: An Interim Analysis

Cutaneous T-cell lymphoma (CTCL) is a heterogenous group of non-Hodgkin T-cell lymphomas with predominant skin involvement. Mycosis fungoides and Sézary syndrome are the most common subtypes and present with a wide spectrum of cutaneous and extra-cutaneous manifestations. Early-stage disease is often controlled with skin-directed therapies while advanced-stage disease can be treatment-refractory and often requires multiple lines of systemic therapy. It is therefore of great interest to identify early predictors of treatment response to tailor therapeutic management decisions. Modified Severity-Weighted Assessment Tool (mSWAT) scoring and lymph node evaluation are important components of treatment response assessment in clinical practice and in trials. A major limitation of current assessment methods is the use of relative changes in mSWAT and lymph node size which do not account for heterogeneous treatment effects. Novel assessment techniques that reflect the dynamic changes occurring within the tumor environment during treatment have the potential to offer more accurate insights into treatment response than current methods. Among these novel approaches is kinetic modeling of tumor growth rate ( g), which has been validated as a biomarker for treatment response and survival in other types of cancer but has never been used in CTCL. Kinetic modeling provides the benefit of evaluating the simultaneous rates of growth of treatment-resistant cells and regression of treatment-responsive cells. We hypothesized that dynamic changes in lymph node size and mSWAT scores over time could predict response to treatment in CTCL patients. We retrospectively analyzed clinical data and computed tomography scans from 119 patients enrolled in the MAVORIC trial. An open-source imaging platform with integrated semi-automated segmentation algorithms was used to quantify lymph node volumes for each patient. Kinetic modeling was applied to estimate the simultaneous rates of growth ( g) and regression ( d) of lymph node size and mSWAT scores during treatment. Patients were divided into two groups based on g and correlation with time to treatment failure (TTF) was evaluated. Tumor doubling times were estimated using the equation dt = 0.693/ g. For most patients, g and d could be estimated, and these values could be determined early in the treatment course. Volumetric lymph node growth rate had an inverse correlation with TTF (p &amp;lt; 0.0001). Patients with with faster rates of nodal growth (median g = 0.0077 d -1, doubling time = 90 days) had a median TTF of 2.9 months, whereas patients with slower rates of nodal growth (median g = 0.0013 d -1, doubling time = 533 days) had a median TTF of 8.8 months. Rate of growth of mSWAT scores also had an inverse correlation with TTF (p &amp;lt; 0.0001). Those with the fastest rate of increase in mSWAT scores (median g = 0.0057 d -1, doubling time = 122 days) had a median TTF of 2.9 months while those with the slowest rate of increase (median g = 0.0013 d -1, doubling time = 533 days) had a median TTF of 8.5 months. In this interim analysis, we use a novel kinetic model to demonstrate that g correlates with time to treatment failure, suggesting that lymph node and mSWAT growth kinetics may be early predictors of treatment response in CTCL. Our findings have potential implications for both clinical practice and trials. Lymph node and mSWAT growth rates may support clinicians in making early decisions about adapting treatment regimens for individual patients. In clinical trials and early drug development, the incorporation of g as an endpoint may accelerate the recognition of promising drug candidates. Our findings require validation in a larger cohort as well as prospective studies.

Topical Ruxolitinib for Chronic Cutaneous GvHD: Promising Results of a Phase 2 Clinical Trial

Background: Oral ruxolitinib is FDA-approved for the treatment of acute and chronic graft-versus-host disease (cGvHD), and ruxolitinib cream has been approved for the treatment of atopic dermatitis and vitiligo. Topical corticosteroids are the mainstay of skin-directed therapy for cutaneous cGvHD but are associated with significant side effects, and may incompletely treat cutaneous cGvHD thereby prompting the use of systemic therapies. Methods: We conducted a single-center, phase 2 prospective, randomized, double-blind trial evaluating the efficacy and safety of ruxolitinib 1.5% cream in patients ≥12 years old with cutaneous nonsclerotic (lichen planus-like, poikilodermatous) and superficially sclerotic (lichen sclerosus, morphea-like) cGvHD with ≥2% of body surface area (BSA) affected. Patients were eligible if systemic therapy, when applicable, was stable for ≥4 weeks and concurrent topical therapy (including phototherapy) was not used. Patients were randomly assigned (1:1) to receive ruxolitinib 1.5% cream to the left or right side of face/body with placebo vehicle cream to contralateral side twice daily for 28 days. The primary endpoint was efficacy at Day 28, as measured by BSA of the GvHD rash on the side of face/body treated with ruxolitinib cream vs contralateral side treated with vehicle. Secondary endpoints included Physician's Global Assessment (PGA), and Composite Assessment of Index Lesion Severity (CAILS) at Days 14 and 28. For the exploratory endpoint, skin samples were noninvasively collected using the SmartSticker™ and RNA-sequencing was used to investigate gene expression differences between 1) ruxolitinib and vehicle treatments, and 2) responders (PGA 0-4) and nonresponders (PGA 5-6) at Day 28. Results: Between 6/28/19 - 9/08/22, 24 patients (median age 47.5 years (range 18-78 years; 11 [46%] male) underwent randomization; Day 14 and Day 28 assessments were completed by 22 and 23 patients, respectively. Most patients had a history of acute leukemia (N=16 [67%]) or non-Hodgkin lymphoma (N=4 [16%]). Median time from transplant to enrollment was 455 days (IQR 357-1020), and from cGvHD onset to enrollment 132 days (IQR 19-384). Most patients had cutaneous nonsclerotic cGvHD (N=21, 87%) with lichen planus-like (N=11), papulosquamous (N=7), and maculopapular rash/erythema features (N=3). Three patients had lichen sclerosus-like cGvHD. Patients were heavily pretreated and had a median of 2 prior systemic treatments. Most patients had failed ≥2 topical therapies: 88% failed topical steroids, 42% topical calcineurin inhibitors, and 29% phototherapy. BSA of cGvHD on the treatment side compared to the vehicle side was significantly improved from Day 1 (14.4 vs 14.5% on treatment/vehicle; p=0.12) to Day 14 (7.7 vs 10.4; p=0.002) to Day 28 (6.2 vs 10.4; p=0.003), respectively. Both secondary endpoints were significantly improved with treatment starting on Day 14 and continuing into Day 28 (PGA D1: 5 treatment vs 5 vehicle; D14: 2.7 vs 3.8, p=0.002; D28: 1.9 vs 3.7, p=0.0004. CAILS D1: 15 treatment vs 15.3 vehicle, p=0.12; D14: 6.9 vs 11, p=0.0009; D28: 5.8 vs 10.6, p=0.004). Seven patients experienced 16 treatment-emergent AEs, the most commonly observed was orofacial dermatitis attributed to protective mask use (n=2). One grade 1 headache was possibly attributed to therapy. RNA sequencing from 22 ruxolitinib- and vehicle- treated patient pairs at Day 28 identified 324 differentially expressed genes (DEGs, fold change (FC)&amp;gt; 2; adjp=0.05) with primary pathway differences in translocation of ZAP-70 to immunological synapse, PD-1 signaling, and Th17 cell differentiation ( Figure 1). Additionally, 288 DEGs (FC&amp;gt;2; p=0.05) were identified between responders (n = 17) and nonresponders (n = 5) at Day 28 ( Figure 2) with pathway differences in IL-12 signaling. Responders had upregulated expression of LCP1 and SOD2, while nonresponders had upregulation in CA1 and SNRPA1. Conclusions: This is the first study to characterize the effect of topical JAK1/2 blockade on cutaneous cGVHD. Ruxolitinib 1.5% cream was safe and effective compared to placebo in treating cutaneous nonsclerotic and superficially sclerotic GvHD. Responders to ruxolitinib cream had genomic signature differences in IL-12 signaling from nonresponders. These encouraging results support a larger clinical trial to further evaluate the efficacy and safety of topical ruxolitinib in patients with cutaneous cGvHD.

HyBryte™ use in early-stage cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is a rare type of non-Hodgkin lymphoma of the skin, where at later stages skin-homing malignant T-cells affect lymph nodes, blood, and visceral organs. Even though early CTCL does not affect survival, it can progress to more advanced stages of disease and have a significant effect on the quality of life of patients. Although expectant management is a treatment consideration in early disease stages, most patients cycle through different skin-directed therapies throughout their lifetime. It can become a challenge to manage the serious and accumulating risk of side effects of these therapies, including various skin cancers and skin damage. Adverse effects from topical therapies limit their long-term utility. Thus, there is an unmet need for well-characterized therapies that have a rapid onset of action and minimal long-term/cumulative side effect profile. Most recently, the results of a Phase 3 study of topical HyBryte™ as a potential treatment for CTCL demonstrated its efficacy and safety profile. This article summarizes what is known about HyBryte™, focuses on its mechanism of action, and highlights its effectiveness, safety, and tolerability in the context of other current FDA-approved topical therapies for CTCL.

Early intervention of extracorporeal photopheresis for advancing/progressing cutaneous T-cell lymphoma.

Patients with cutaneous T-cell lymphoma with progressive disease typically undergo a series of skin-directed and systemic therapy regimens during cycles of response and relapse. Extracorporeal photopheresis (ECP) is an effective and safe systemic treatment option, often reserved for later stages of disease and typically employed after failure of several other therapies. ECP has benefits in response rate, time to next treatment, and tolerability that may support its use earlier in the treatment cycle for advancing/progressing disease.

Characteristics of Primary Cutaneous Lymphoma in Italy: A Tertiary Care, Single-Center Study.

Data on primary cutaneous lymphomas (PCLs) patients in the Italian population are limited, and, despite the existence of several treatment options, the management of those patients remains challenging. Our study aimed to investigate the clinical and therapeutic features of PCL patients in a referral center in Italy. We conducted a retrospective study on 100 consecutive PCL patients between January 2017 and December 2022. The mean (SD) age of our cohort was 70.33 (14.14) years. Cutaneous T-cell lymphomas (CTCLs) represented 65% of all cases; the majority were mycosis fungoides (42%), followed by cases of Sezary syndrome (10%) and primary cutaneous anaplastic large cell lymphoma (4%). Cutaneous B-cell lymphomas (CBCLs) accounted for 35 % of PCLs, with 15 cases of primary cutaneous follicle center lymphoma, 10 cases of primary cutaneous diffuse large B-cell lymphoma leg type, and 9 cases of marginal zone B-cell lymphoma. A higher frequency of pruritus (p = 0.008) and higher peripheral blood levels of beta-2 microglobulin (p ≤ 0.001) and lactate dehydrogenase (p = 0.025) were found in CTCLs compared to those of CBCLs. Considering all therapeutic lines performed, treatments were extremely heterogeneous and skin-directed therapies represented the most frequently used approach. Our study confirms the distribution of PCL subtypes formerly reported in the literature and highlights the utility of real-life data in treatments to improve the current management of PCL patients.

Mycosis Fungoides: Case report of progression successfully treated with liposomal doxorubicin

Mycosis fungoides is the most common primary cutaneous T-cell lymphoma. It is a non-Hodgkin lymphoma that begins in the skin and is characterized by a slow clinical evolution of three stages: macules, plaques and tumors. The advanced stage includes lymph node, visceral, or blood involvement, and requires skin-directed therapy associated with systemic medications. The case of a 49-year-old female patient with a diagnosis of mycosis fungoides in the malar region since July 2019 is presented, initially treated between November 2019 and March 2020 with 3 cycles of the CHOP chemotherapy regimen - cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin) and prednisone without achieving any clinical response. Subsequently without follow-up or treatment. In February 2023, progression of the disease was documented due to worsening of the lesion in the malar region and involvement of the glutes and back, additionally with cervical lymphadenopathy but without bone marrow involvement. She is considered a candidate for liposomal doxorubicin, with which she has completed 5 cycles to date with excellent clinical response. Current reassessment studies using positron emission tomography show complete tumor response. A bone marrow transplant is the therapeutic option that is being considered at the moment.

Cutaneous T-Cell Lymphoma (Mucosal Fungoid) as First Manifestation of Metastatic Lymphoma

Primary cutaneous T-cell lymphomas are a diverse group of extranodal non-Hodgkin lymphomas characterized by the infiltration of malignant T-cells within the skin. Mycosis fungoides (MF), the most common subtype, typically presents with skin-limited manifestations. However, in a subset of cases, it can herald the onset of systemic lymphoma, representing a diagnostic challenge for clinicians. This article explores a compelling clinical case of primary cutaneous T-cell lymphoma, specifically mycosis fungoides, manifesting as an initial sign of disseminated or metastatic lymphoma. We dissect the complex diagnostic and management considerations associated with this unique clinical presentation. Through a review of the current literature and clinical insights, we delineate the clinical, histopathological, and immunophenotypic features that facilitate the diagnosis and differentiation of MF as an isolated cutaneous entity from MF with secondary extracutaneous involvement. The article highlights the critical role of multidisciplinary collaboration among dermatologists, oncologists, and pathologists in achieving timely and accurate diagnosis and guiding therapeutic decisions. It further underscores the evolving landscape of treatment options for this challenging subset of patients, ranging from skin-directed therapies to systemic agents. Additionally, this case provides a stark reminder of the importance of ongoing surveillance, as the clinical course of MF may unpredictably transition to a more aggressive form. In conclusion, this case serves as a vivid illustration of mycosis fungoides with mucosis fungoides as its initial presentation, challenging the conventional understanding of primary cutaneous T-cell lymphomas. The intricate interplay of clinical, histological, and immunophenotypic data informs the diagnosis and informs the broader clinical community about the potential metamorphosis of cutaneous lymphomas into systemic lymphomas. Understanding such cases is crucial for early intervention and improved patient outcomes.

Advances in the treatment of mycoses fungoides and Sézary syndrome: a narrative update in skin-directed therapies and immune-based treatments.

Mycoses fungoides (MF) and Sézary syndrome (SS) are cutaneous T-cell lymphomas that are often challenging to manage given the absence of reliably curative therapies, at times high symptom burden with significant detriment to quality of life, and need for ongoing treatment for disease and symptom control. Recent developments in skin-directed treatments include optimizing the use of existing topical therapies, the introduction of known dermatological agents and treatment modalities for the specific treatment of MF/SS (such as mechlorethamine gel, calcineurin inhibitor creams, and photodynamic therapy), and novel local and topical agents. For advanced disease, dedicated clinical trials have translated to exciting progress, leading to the approval of brentuximab vedotin (2017) and mogamulizumab (2018) for relapsed MF/SS. Additional studies of other active systemic agents, including various cellular therapies, represent further attempts to add to the therapeutic armamentarium in treating MF/SS. In this review, we highlight these recent advancements, ranging from optimization of skin-directed therapies to the introduction of novel systemic agents. We focus on therapies approved in the preceding five years or under investigation in advanced-phase clinical trials.

Mycosis Fungoides in Solid-Organ Transplant Recipients: A Multicenter Retrospective Cohort Study

Background: Mycosis fungoides (MF) in solid-organ transplant recipients (SOTRs) is rare, with limited data on disease characteristics. Objective: The aim was to study the characteristics of MF in SOTRs with an emphasis on the immunosuppressive therapy. Methods: A retrospective cohort of patients diagnosed with MF, who were also SOTRs, were followed at 3 cutaneous lymphoma outpatient clinics, between January 2010 and February 2022. Results: Ten patients were included (7 male; median ages at transplantation and at diagnosis of MF were 33 and 48 years, respectively; 40% were diagnosed before the age of 18 years). Median time from transplantation to diagnosis of MF was 8 years (range 0.5–22). Transplanted organs and immunosuppressive treatments included: liver (n = 5; 4 treated with tacrolimus, 1 with tacrolimus and prednisone), kidney (n = 3), liver and kidney (n = 1), and heart (n = 1), all treated with mycophenolic acid, tacrolimus, and prednisone. Nine had early-stage MF (IA – 4, IB – 5; 40% with early folliculotropic MF), treated with skin-directed therapies, in 2 combined with acitretin, achieving partial/complete response. One patient had advanced-stage MF (IIIA) with folliculotropic erythroderma, treated with ultraviolet A and narrow-band ultraviolet B with acitretin, achieving partial response. Immunosuppression was modified in 3. At last follow-up (median 4 years, range 1–8), no stage progression was observed; 5 had no evidence of disease, 5 had active disease (IA/IB – 4, III – 1). Conclusions: MF in SOTRs is usually diagnosed at an early stage, with overrepresentation of folliculotropic MF, and of children. Immunosuppressive therapy alterations, not conducted in most patients, should be balanced against the risk of organ compromise/rejection. Disease course was similar to MF in immunocompetent patients, during the limited time of follow-up.