Early-stage Mycosis Fungoides Research Articles

Multiple skin-colored facial papules in a child

Multiple skin-colored facial papules in a child

Prognostic factors for disease remission in early-stage mycosis fungoides: A retrospective cohort study in a Mexican population

Mycosis fungoides (MF) is the most frequent cutaneous T-cell lymphoma in 60% to 65% of all cases. The incidence reported in Mexico is 0.14% per year.1 It affects generally male gender with a ratio 1.6:1 in their fifth decade.2 Most patients are diagnosed in the early stage of disease. First-line treatment of early-stage disease consists of skin-directed therapies. This study aimed to determine prognostic factors for disease remission in early-stage MF.

Application of the current diagnostic algorithm for early mycosis fungoides to a single center cohort: Identification of challenges and suggestions for modification.

Diagnosing early-stage mycosis fungoides (MF) remains a significant challenge. The International Society for Cutaneous Lymphomas (ISCL) proposed an algorithm for diagnosing early MF incorporating clinical and histopathologic characteristics, as well as immunohistochemistry and molecular studies. Here we aim to examine the diagnostic utility of the ISCL algorithm. In this single-center retrospective review, the ISCL algorithm was applied to 28 patients diagnosed with early-stage MF. Immunohistochemistry and molecular studies were not performed for all patients, so a subgroup analysis was conducted including 18 patients in whom both studies had been performed. We calculated the diagnostic sensitivity of the algorithm. Subsequently, we examined how modifying the algorithm's histopathologic criterion from epidermotropism without spongiosis to epidermotropism influenced its sensitivity. Forty-three percent (12/28) of the cohort and 50% (9/18) of the subgroup met the algorithm's diagnostic threshold. When the algorithm was modified, 71% of the cohort and 89% of the subgroup met the algorithm's threshold. While the ISCL algorithm is useful in diagnosing early-stage MF, its sensitivity remains suboptimal. Further refinement of the algorithm to capture spongiotic subtypes of MF may improve its diagnostic value.

Activity and safety of topical pimecrolimus in patients with early stage mycosis fungoides (PimTo-MF): a single-arm, multicentre, phase 2 trial

The calcineurin pathway is often activated in mycosis fungoides. We aimed to assess the activity and safety of topical pimecrolimus, a calcineurin inhibitor, in patients with early mycosis fungoides. PimTo-MF was a single-arm, multicentre, phase 2 trial done at six medical centres in Spain. Patients (aged ≥18 years) had histologically confirmed early mycosis fungoides (stages IA-IIA) and an Eastern Cooperative Oncology Group performance status of 0-1. Key exclusion criteria included the use of concurrent treatments for mycosis fungoides, including sunbathing, topical or systemic corticosteroids, and other calcineurin inhibitors. Patients applied topical pimecrolimus 1% cream on their skin lesions twice daily for 16 weeks (1 g per 2% of body surface), with subsequent follow-up of 12 months. Dosage modifications were not allowed. To evaluate adherence to the treatment, patients were instructed to return all empty tubes to the hospital (as per drug accountability protocols). The primary endpoint was the overall response ratein the intention-to-treat population. PimTo-MF is registered with EudraCT, 2014-001377-14, and is complete. Between March 1, 2015, and Sept 30, 2016, 39 patients were enrolled. All patients were assessable, with a median age of 51·5 years (IQR 45-62), and the population was predominantly male (24 male [62%], 15 female [38%]). Median follow-up after baseline was 5·7 years (IQR 5·7-6·2). 22 (56%) of 39 patients had an overall response (one complete response, 21 partial responses). Responses were observed across IA (14 [54%] of 26 patients) and IB (eight [73%] of 11 patients) clinical stages, but not IIA. Topical pimecrolimus was well tolerated and no patient required a dose reduction or discontinued treatment because of unacceptable drug-related toxicity. No patients were lost to follow-up or discontinued treatment. 13 (33%) of 39 patients reported adverse events; transitory mild burning or pruritus (grade 1) was the most common, seen in eight (21%) patients. In three (8%) of these patients, the burning or pruritus was considered related to treatment. No grade 4 or 5 adverse events were observed. Pimecrolimus 1% cream seems active and safe in patients with early stage mycosis fungoides. Our findings should be taken with caution until long-term follow-up data are obtained that confirm the safety of this treatment. Further controlled clinical trials are warranted to confirm these results. Instituto de Salud Carlos III and the European Regional Development Fund. For the Spanish translation of the abstract see Supplementary Materials section.

Future role of topical pimecrolimus in early stage mycosis fungoides?

Effective therapeutic options are scarce for early stage mycosis fungoides. Guidelines recommend skin-directed therapies in the early stages of mycosis fungoides (stages IA–IIA). In Europe, skin-directed therapies for early stage mycosis fungoides were restricted to topical corticosteroids, phototherapy, or radiotherapy,1–3 until the European Commission approved chlormethine gel 160 μg/L for the topical treatment of mycosis fungoides type cutaneous T-cell lymphoma in adults in 2017.

Does CADM1 Immunohistochemistry Distinguish Mycosis Fungoides from its Closest Mimickers?

BackgroundImmunohistochemistry (IHC) sometimes fails to distinguish clinically ambiguous cases of evolving patch‐stage mycosis fungoides (MF) from relatively common, non‐neoplastic inflammatory skin diseases (ISD), particularly spongiotic dermatitis (SD), psoriasis (PSO), and pityriasis lichenoides (PL). CADM1 (cell adhesion molecule 1) is a tumor suppressor gene implicated in the pathogeneses of solid skin tumors, visceral malignancies, and peripheral T‐cell lymphomas. Recent data suggest that CADM1 IHC expression could help distinguish early‐stage MF from ISD.DesignThis pilot study sought to determine whether CADM1 IHC distinguishes MF from ISD in clinically‐annotated cases from our archives. MF (n=14), PL (n=10), PSO (n=10), and SD (n=10) were stained with CADM1. Using appropriate controls and antibody optimization, two pathologists established consensus scores in each case for percentage of lymphocytes staining with CADM1 and CADM1 staining intensity. The localization of CADM1‐positive cells (epidermis including junction and dermis) was also noted.ResultsThere were no differences in CADM1 expression pattern or intensity between groups. All cases showed moderate to strong nuclear CADM1 expression in ≥75% of lymphocytes in both the dermis and epidermis. Some intraepidermal lymphocyte nuclei were challenging to detect on CADM1‐stained slides given uniform moderate‐intensity staining of background keratinocyte nuclei.ConclusionThe challenge of distinguishing evolving patch‐stage MF from ISD facilitates demand for novel and readily available diagnostic tests. Although recent data have suggested that differential expression of CADM1 distinguishes MF from ISD, there was no difference in lymphocyte CADM1 expression and distribution between any of the groups included in our pilot study. Furthermore, evaluation of CADM1 expression in intraepidermal lymphocytes was challenging given background keratinocyte expression.

Parapsoriasis-A Diagnosis with an Identity Crisis: A Narrative Review.

Parapsoriasis is an uncommon inflammatory skin disease characterized by chronic patches that may be resistant to therapy. It was primarily introduced and classified 120 years ago, and the original classification incorporated parapsoriasis and pityriasis lichenoides under the umbrella term parapsoriasis. After a major change in classification, parapsoriasis now exclusively refers to small plaque parapsoriasis (SPP) and large plaque parapsoriasis (LPP). However, debates still frequently occur regarding various nomenclatures and classifications used by different authors. Moreover, parapsoriasis may progress to overt cutaneous lymphoma, most commonly mycosis fungoides (MF), and it is very difficult to distinguish these two conditions despite modern histologic and molecular testing techniques.As parapsoriasis is a rare disease, there is a lack of studies and clinical guidelines to assist physicians in clinical practice. In our comprehensive review, we review several aspects of parapsoriasis, from the history of nomenclature and classification, clinical characteristics, immunohistopathology, and advanced molecular techniques for the diagnosis of this condition, to the most current treatments. We also propose a scheme for distinguishing parapsoriasis from early-stage MF in this review.

Mass Cytometric Analysis of Early-Stage Mycosis Fungoides.

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma. Early-stage disease is characterized by superficial infiltrates of small- to medium-sized atypical epidermotropic T lymphocytes that are clonal related. Nevertheless, the percentage of atypical T cells is low with many admixed reactive immune cells. Despite earlier studies, the composition and spatial characteristics of the cutaneous lymphocytic infiltrate has been incompletely characterized. Here, we applied mass cytometry to profile the immune system in skin biopsies of patients with early-stage MF and in normal skin from healthy individuals. Single-cell suspensions were prepared and labeled with a 43-antibody panel, and data were acquired on a Helios mass cytometer. Unbiased hierarchical clustering of the data identified the major immune lineages and heterogeneity therein. This revealed patient-unique cell clusters in both the CD4+ and myeloid cell compartments but also phenotypically distinct cell clusters that were shared by most patients. To characterize the immune compartment in the tissue context, we developed a 36-antibody panel and performed imaging mass cytometry on MF skin tissue. This visualized the structure of MF skin and the distribution of CD4+ T cells, regulatory T cells, CD8+ T cells, malignant T cells, and various myeloid cell subsets. We observed clusters of CD4+ T cells and multiple types of dendritic cells (DCs) identified through differential expression of CD11c, CD1a, and CD1c in the dermis. These results indicated substantial heterogeneity in the composition of the local immune infiltrate but suggest a prominent role for clustered CD4–DC interactions in disease pathogenesis. Probably, the local inhibition of such interactions may constitute an efficient treatment modality.

Treatment of early-stage mycosis fungoides with oral bexarotene and phototherapy: A systematic review and meta-analysis.

Mycosis fungoides (MF) is a rare subtype of non-Hodgkin lymphoma, for which no standard treatment exists. The objective of this study is to provide evidence-based recommendations for adult patients with early-stage MF treated with oral bexarotene and phototherapy. A systematic review and meta-analysis was conducted utilizing studies identified via Embase, Pubmed, Web of Science, and the Cochrane Library from inception to April 2020 to evaluate the clinical efficacy and adverse events of oral bexarotene and phototherapy. Of 645 abstracts retrieved, 17 full-text articles with 143 subjects were included for analysis. There were nine case reports, five retrospective cohort studies, two prospective cohort studies, and one randomized controlled trial. Most subjects were men (24.48%) with stage IB disease (54.4%), and the mean age at presentation was 63. One patient had folliculotropic disease. The retrospective studies' analysis included 67 subjects and indicated that the partial response was 40.36% (95% CI 18.24-64.92), complete response was 34.06% (95% CI 10.73-62.56), and overall response was 64.48% (95% CI 48.56-78.89). Side effects from bexarotene were hypertriglyceridemia (54%), hypothyroidism (50%), and hypercholesterolemia (46%). Similar results were noted in the prospective studies. The literature consists mostly of uncontrolled studies, which suggest that combination therapy with oral bexarotene and phototherapy is a therapeutic option. Future randomized control studies with longer follow-up and standardized definitions of treatment responses and dosages are needed to support the development of evidence-based approaches for the treatment of early-stage MF.

Topical Bimiralisib Shows Meaningful Cutaneous Drug Levels in Healthy Volunteers and Mycosis Fungoides Patients but No Clinical Activity in a First-in-Human, Randomized Controlled Trial.

Simple SummaryPrimary cutaneous T-cell lymphomas (CTCLs) are a group of lymphomas that present in the skin without extracutaneous localizations at diagnosis. Recent studies in clinical and translational research augmented our understanding of the pathogenesis and pathophysiology of different subtypes of CTCL, enabling the identification of novel therapeutic drug targets. In this study, the primary focus is on bimiralisib gel 2%, a dual pan-class PI3K/mTOR inhibitor, and its potential to inhibit the PI3K/AKT/mTOR signaling pathway as a novel therapeutic target in CTCL.Mycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human study was to evaluate safety, efficacy, cutaneous and systemic pharmacokinetics (PK) of topical bimiralisib in healthy volunteers (HVs) and MF patients. In this trial, a total of 6 HVs and 19 early-stage MF patients were treated with 2.0% bimiralisib gel and/or placebo. Drug efficacy was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score, supported by objective measuring methods to quantify lesion severity. PK blood samples were collected frequently and cutaneous PK was investigated in skin punch biopsies on the last day of treatment. Local distribution of bimiralisib in HVs showed a mean exposure of 2.54 µg/g in the epidermis. A systemic concentration was observed after application of a target dose of 2 mg/cm2 on 400 cm2, with a mean Cavg of 0.96 ng/mL. Systemic exposure of bimiralisib was reached in all treated MF patients, and normalized plasma concentrations showed a 144% increased exposure compared to HVs, with an observed mean Cavg of 4.49 ng/mL and a mean cutaneous concentration of 5.3 µg/g. No difference in CAILS or objective lesion severity quantification upon 42 days of once-daily treatment was observed in the MF patient group. In general, the treatment was well tolerated in terms of local reactions as well as systemic adverse events. In conclusion, we showed that topical bimiralisib treatment leads to (i) meaningful cutaneous drug levels and (ii) well-tolerated systemic drug exposure in MF patients and (iii) a lack of clinical efficacy, in need of further exploration due to numerous unknown factors, before depreciation of topical bimiralisib as a novel therapeutic drug for CTCLs.

Paediatric mycosis fungoides - characteristics, management and outcomes with particular focus on the folliculotropic variant.

The literature on paediatric mycosis fungoides (MF) and especially its folliculotropic variant (FMF) is sparse. To describe the clinical manifestations, treatments, outcomes and long-term course of paediatric MF, including FMF. A retrospective analysis was conducted of all consecutive MF patients diagnosed at ≤18 years attending two medical centres in 1995-2015. The cohort included 71 patients, all but two of whom had early-stage disease: hypopigmented (55%), folliculotropic (42%) and classical MF (39%), alone or in combination. The head and neck area were involved in 43% of patients with early-stage FMF compared to 12% of the non-FMF group (P = 0.004). There was no difference in the involvement of other body areas between the groups. Pruritus, although mild, was more often recorded among patients with early-stage FMF compared to non-FMF (58% vs. 29%, respectively, P = 0.02). Complete response (CR) was achieved in 60 of the 69 patients with early-stage MF (87%) after an average of 1.8 treatment modalities. NBUVB was the most administered treatment to non-FMF patients with CR rates of 63% vs. 29% of FMF patients (P = 0.04). Systemic/bath PUVA and UVA+NBUVB were the most administered treatments to FMF patients with CR rates of 60% vs. 81% for non-FMF patients (P = 0.17). During a mean follow-up of 9.2 years (range 1-24), stage progression was observed in four (6%) of the patients with early-stage disease, two of whom (all FMF) to advanced stage. Paediatric MF presents as an early-stage disease with over-representation of hypopigmented and FMF variants. NBUVB and UVA-based therapies yield good response rates in non-FMF and FMF patients, respectively. Disease course is indolent, and even on relatively long follow-up, it has a very low progression rate from early to advanced-stage disease, occurring in patients with FMF. We propose a treatment algorithm for paediatric MF.

New developments in skin-directed treatments of cutaneous T-cell lymphoma

The therapeutic approach for mycosis fungoides, the most common type of primary cutaneous T-cell lymphoma, is based mainly on the stage of the disease, and skin-directed treatment is recommended by all international guidelines as the first-line of treatment for early-stage disease. Skin-directed treatments may be also given in combination with systemic therapies in early-stage mycosis fungoides patients recalcitrant to different types of skin-directed treatments, or in certain patients with high-risk features. Advanced-stage mycosis fungoides is treated mainly with systemic treatments, which may be combined with skin-directed treatments.Due to the rarity of mycosis fungoides, controlled clinical trials of the different skin-directed treatment modalities are almost non-existent, with a few exceptions, and therefore recommendations are largely based on cohort studies and expert opinion.This paper reviews the new developments in skin-directed treatments and provides an update on new studies of already well-known therapies, and an update on novel treatments.

Acceleration of skin involvement may predict disease progression in early-stage mycosis fungoides: A retrospective cohort study

To the Editor: Many clinicians have observed that acceleration of body surface area (BSA) involvement in mycosis fungoides correlates with disease progression.1 The goal of this study is to quantify acceleration and determine if this parameter can predict progression and/or assure patients that they are unlikely to progress.

Randomized Mechlorethamine/Chlormethine Induced Dermatitis Assessment Study (MIDAS) Establishes Benefit of Topical Triamcinolone 0.1% Ointment Cotreatment in Mycosis Fungoides.

IntroductionTreatment of early-stage mycosis fungoides (MF) requires safe, skin-directed therapies. Medication side effects can lead to underutilization of effective therapies. The objective of this study was to assess the use of topical triamcinolone 0.1% ointment as a means of reducing contact dermatitis associated with topical mechlorethamine/chlormethine gel for the treatment of MF.MethodsThis prospective, randomized, open-label study evaluated 28 adults with mycosis fungoides who were eligible for treatment with topical mechlorethamine/chlormethine gel from December 17, 2017 to December 23, 2020. Patients were treated for 4 months with clinical follow-up through 12 months. Patients had half of their lesions also treated with topical triamcinolone 0.1% ointment (while the other half were treated with mechlorethamine/chlormethine alone). The study was self-controlled with separate lesions in the same patient receiving each treatment arm. Treatment arms were determined by the flip of a coin.ResultsTwenty-eight patients enrolled (17 men (61%) and 11 women (39%)). Demographics included 25 White, 2 African Americans, and 1 Asian patient. Twenty-five completed the 12-month follow-up. Triamcinolone 0.1% ointment led to increased tolerability of mechlorethamine/chlormethine gel but did not change the efficacy of mechlorethamine/chlormethine. There was a statistically significant 50% decrease in dermatitis (SCORD score) at month 2 in the triamcinolone-treated arm.ConclusionsTopical triamcinolone ointment is a helpful adjuvant therapy when treating patients with topical mechlorethamine/chlormethine gel. It diminishes inflammation and does not reduce efficacy. The peak incidence of dermatitis in the study occurred in the second and third months.Trial RegistrationClinicalTrials.gov identifier, NCT03380026.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-022-00681-6.

Immunohistochemical Expression Patterns of CD45RO, p105/p50, JAK3, TOX, and IL-17 in Early-Stage Mycosis Fungoides.

The morphologic changes in early-stage mycosis fungoides (MF) might overlap with benign inflammatory dermatitis (BID). Previous studies have described altered expression patterns of several proteins in MF, but their diagnostic significance is uncertain. This study aims at examining the frequency of expression of CD45RO, NFkB-p105/p50, JAK3, TOX, and IL-17 proteins by immunohistochemistry. The cohorts included 21 patients of early-stage MF and 19 with benign BID as a control group. CD45RO was positive in all patients of MF and BID. NFkB-p105/p50 showed normal cytoplasmic staining, indicating an inactive status in all patients of both groups. JAK3 was positive in 3 (14%) MF and in 17 (89%) BID patients (p = 0.003). TOX was expressed in 19 (90%) and 13 (68%) patients of MF and BID, respectively (p = 0.120). IL-17 was detected in 13 (62%) MF and in 7 (37%) BID patients (p = 0.056). Co-expression of TOX and IL-17 was seen in 11 (52%) MF patients but in only 3 (16%) BID patients, which was statistically significant (p = 0.021). We conclude that a double expression of TOX and IL-17 may support the diagnosis of MF in the right clinicopathologic setting, while none of the immunohistochemical stains alone provided a significant discrimination between MF and BID.

TOX Outperforms FOXP3, CD4 and GATA3 in Histopathological Diagnosis of Early Mycosis Fungoides.

Mycosis fungoides (MF) is the most common type of cutaneous lymphoma. The early stage of MF is a difficult diagnostic case, as it is often confused with many benign inflammatory dermatoses (BID). The study aimed to evaluate the diagnostic utility of TOX, FOXP3, CDD4 and GATA3 in differentiating early stages of MF from histologically overlapping BID lesions. A retrospective cross-sectional study was performed, in which immunohistochemistry (IHC) was used to evaluate the expression of TOX, FOXP3, CD4 and GATA3 in formalin-fixed paraffin-embedded (FFPE) sections of skin lesions from 30 cases with BID and 30 patients with early-stage MF. The association between TOX expression and early-stage MF was statistically significant (P < 0.001). TOX had the highest sensitivity of 96.77% and accuracy of 85.71% in diagnosis of MF; followed by CD4 with sensitivity of 85.71% and accuracy of 78.95%; and then, GATA3 with sensitivity of 76.7% and finally FOXP3 with sensitivity of 70.0%. TOX is suggested to be of higher diagnostic value in the early stages of MF than the conventionally used CD4 and other markers examined.

Features and trends of infiltrate formation in the dermis of patients in the early stages of mycosis fungoides

<h3>АКТУАЛЬНОСТЬ</h3> Одним из наиболее сложных вопросов в онкодерматологии является выявление ранней (эритематозной) стадии грибовидного микоза (ГМ), характеризуемой появлением пятен на коже и наличием умеренных паравазальных инфильтратов в сосочковом слое дермы с локальным обнаружением эпидермотропизма при сохранности эпидермиса. В соответствии с рекомендациями ISLE-EORTC выделяют ранние стадии ГМ: IA, IB и IIA, однако в литературе отсутствуют сведения о дифференцированной патоморфологической картине. <h3>ЦЕЛЬ ИССЛЕДОВАНИЯ</h3> Выявление особенностей формирования инфильтрата и определение количественных критериев выраженности лимфопролиферативного процесса в дерме больных при ГМ стадий IA, IB и IIA. <h3>МАТЕРИАЛ И МЕТОДЫ</h3> В УрНИИДВиИ (2018–2021 гг.) проведены клинические и патоморфологические исследования, позволившие установить ГМ I стадии у 30 больных. Изучено 150 имиджей, иммунофенотипирование которых выполнено с применением моноклонального антитела CD3 с целью определения выраженности пролиферативного процесса Т-лимфоцитов. Для количественных исследований использована программа SIAMS Photolab (Россия), позволяющая определить объемную долю изучаемого объекта в каждом из исследуемых полей зрения с вычислением средней объемной доли (СОД) и среднего квадратического отклонения (СКО). <h3>РЕЗУЛЬТАТЫ</h3> Клинические, патоморфологические и морфометрические исследования показывают различия в течении лимфопролиферативного процесса на ранних стадиях ГМ в начале заболевания и по прошествии некоторого времени. Для ранних стадий ГМ характерно постепенное увеличение площади лимфоидного инфильтрата в дерме, при этом СОД клеток CD3⁺ при ГМ IA составила 0,057 (СКО 0,014), при ГМ IB — 0,136 (СКО 0,024); при ГМ IIA — 0,230 (СКО 0,023). <h3>ЗАКЛЮЧЕНИЕ</h3> При комплексном использовании клинических, патоморфологических и морфометрических исследований возможно получение объективных критериев дифференцированной диагностики ранних стадий ГМ.

Risk Factors for Progression from Early to Advanced Stage Mycosis Fungoides: A Single Center Retrospective Analysis at the Winship Cancer Institute of Emory University

Introduction:Advanced stage mycosis fungoides (MF) has a median survival of 3-5 years, while early stage MF is a chronic disease typically associated with an excellent prognosis and a median survival of 20 years or more. Prior studies suggest approximately 20% of early stage MF may progress to advanced stage, but risk factors for progression remain poorly studied, particularly among African American (AA) patients. We aimed to identify clinic features associated with progression to advanced stage MF in a large urban medical center.MethodsWe performed a retrospective review of 388 patients with early stage (1A-2A) MF at the Winship Cancer Institute of Emory University diagnosed between 1970 and 2021. Clinical data collected from the electronic medical record included demographics, laboratory values, disease characteristics, and therapy. Our primary endpoint was to identify variables associated with progression to advanced stage MF. Progression to advanced stage was defined as a highest overall TNMB stage of 2B-4B. Overall survival (OS) was measured from time of diagnosis to date of death or last follow-up. Kaplan-Meier curves for OS were generated for the whole cohort and by progression group. Descriptive analysis was performed for each variable, and a comparison between patients who did or did not progress to advanced stage was performed using ANOVA for numerical covariates and chi-square test for categorical covariates. The association of baseline variables with OS was modeled by Cox proportional hazards model and multivariable analyses were performed on significant variables.ResultsAmong 388 patients, the median follow up was 5 years (range 0-51). There was even distribution among male (49.0%) and female (51.0%) patients. The median age at diagnosis was 53 years (range 8-95). This population included 41.4% AA, 55.0% White, 2.3% Asian, and 1.3% other races. Stage distribution was as follows: 34.2% (n=133) stage 1A, 51.5% stage 1B (n=200), and 14.2% stage 2A (n=55). Forty-nine patients had hypopigmented MF (45 AA), and 9.4% (n=34) patients developing large cell transformation (LCT) during their disease course. Treatment at diagnosis was topical in 52.3% (n=203), systemic in 1.8% (n=7), radiation in 3.4% (n=13), and multimodality in 29.4% (n=114).Overall, 93 patients (24.1%) progressed to advanced stage. Progression to a higher stage was statistically associated with higher overall TNMB stage at diagnosis (p<0.001), T2 tumor stage (p<0.001), nodal involvement (p=0.031), positive blood flow cytometry (<0.001), T-cell receptor (TCR) clonality in the blood (p=0.014), LCT (p<0.001), and elevated lactate dehydrogenase (LDH) (p<0.001). Patients with hypopigmented MF were less likely to progress (hazard ratio 0.32 (95% CI 0.12-0.84) p=0.020), Sex, race, age, blood stage, and white blood cell count were not associated with risk for progression. Univariate logistic regression is summarized in figure 1.Progression to advanced stage was associated with an increased risk of death (4.75 (0.05-7.38), p < 0.001, figure 2). The median survival for patients who did and did not progress were 11 years (95% CI 7, 15) and 31 years (95% CI 25, not reached), p<0.001 respectively. Other factors associated with an increased risk of death included age > 60 (p <0.001), higher TNMB stage at diagnosis (log rank p<0.001), advanced nodal stage, (p=0.005), positive peripheral blood flow (p=0.010), TCR clonality in the blood (p=0.039), LCT (p< 0.001), elevated LDH (p<0.001), and elevated WBC (p<0.001), while hypopigmented MF was associated with a decreased risk of death (0.28 (0.09-0.90), p=0.021). On multivariable survival analysis controlling for hypopigmented MF, LCT, and stage at diagnosis, only age > 60 (3.32 (2.00-5.51), p<.001) and progression to advanced stage (4.02 (2.38-6.79), p<0.001) remained statistically significant.ConclusionsWe demonstrate that progression to advanced stage is associated with several baseline laboratory and disease characteristics, which bear immediate clinical relevance to the work up and staging of early stage MF. These data suggest that consistent staging and laboratory analyses with imaging for lymph node assessment, peripheral blood flow cytometry, and TCR in all newly diagnosed MF patients may aid in identifying patients at risk for progression to advanced stage disease. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

ICOS Is Widely Expressed in Cutaneous T-Cell Lymphoma and Its Targeting Promotes Potent Killing of Malignant Cells

Background: Advanced cutaneous T-cell lymphomas (CTCLs) remain an unmet medical need. Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate (ADC) linked to monomethyl auristatin E (MMAE), do not deliver significant long-term improvements in patient outcomes. More recently, mogamulizumab and anti-KIR3DL2 provided encouraging results but new targeted therapies are needed. Inducible Co-Stimulator (ICOS), a T-cell costimulatory receptor involved in the development of CTCLs, arouses interest.Methods: We used immunohistochemistry to study ICOS expression in skin biopsies of 23 patients with early-stage mycosis fungoides (MF), 12 with transformed MF (TMF) and 17 with Sézary Syndrome (SS), at diagnosis or in relapse. Skin samples from 12 patients with B-cell lymphomas, 14 with CD30 + lymphoproliferative disease (LPD), 12 with primary cutaneous CD4+ small/medium T-cell lympho-proliferative disorder and 13 with angioimmunoblastic T-cell lymphoma (AITL) were used as controls. ICOS expression by circulating Sézary cells and regulatory T cells (Tregs) in patients with SS was evaluated using flow cytometry and compared to healthy donors (HD) lymphocytes. In 5 patients with SS, we also analyzed concomitant biopsies from involved nodes.Then, we investigated the efficacy of anti-ICOS ADCs generated by coupling murine anti-ICOS 314.8 monoclonal antibodies with MMAE and pyrrolobenzodiazepine (PBD), in comparison to BV. We used ICOS + CTCL cell lines (MyLa, MJ and HUT78), murine xenograft models with MyLa and ICOS + Patient Derived Xenografts (PDXs) from patients with SS and AITL.In order to identify the best anti-ICOS clone that we should develop for a clinical trial, we evaluated the affinity of the antibody on the receptor, the internalization capacity of the antibody using pHAb Reactive Dyes kit (Promega®), and the ability of the antibody to act as an ADC using a secondary conjugate (Mab-ZAP kit, Advanced Targeting Systems®).Results: ICOS was highly expressed by the cutaneous atypical lymphocytic infiltrates in respectively 61%, 75% and 88% of patients with early-stage MF, TMF and SS, such as in all the involved nodes. Double staining experiments which were performed in both skin and lymph node revealed that ICOS expression appears mainly restricted to neoplastic CD4 + T-cells, with rare ICOS +CD8 + T-cells in the tumor micro-environment. ICOS expression by circulating Sézary cells was strong: 69 ± 7.3% versus 38.8 ± 7.1% of non-tumoral CD4 + cells (p<0.009; CI95%: 8.7-51.6); and 31 ± 3.2% of CD4+ cells in HD (p<0.0001; CI95%: 20.3-46.3). Percentages of ICOS + Tregs were significantly higher in patients with SS than in HD.In CTCL cell lines, we observed a significant dose-dependent decrease in cell viability in the presence of anti-ICOS-MMAE (IC50 = 8.2ng/mL) and anti-ICOS-PBD (IC50 = 1.2ng/mL) ADCs. In a mouse xenograft model (MyLa), anti-ICOS-MMAE ADCs provided a longer overall survival (OS) than BV (HR=15.2; CI95%: 3.2-71.1; p<0.0006). Finally, in ICOS + PDXs, anti-ICOS-MMAE ADCs significantly improved OS, and reduced the number of tumor cells in the blood, spleen, and bone marrow. No evidence of ADC toxicity was observed in treated mice.Among 8 different anti-ICOS clones, clone 314.8 had the best affinity on MyLa and MJ cell lines. Clones 53.3, 293.1, 92.17, 88.2 and 279.1 also had good affinity to receptor, whereas clones 145.1 and 121.4 had poor affinity. Using the internalization pHAb reactive dyes kit, we found that clones 314.8, 53.3, 92.17, 88.2 internalized significantly better and faster than the other ones. In order to verify if there is a correlation between internalization capacity and ADC effect, clones 53.3, 92.17 and 145.1 were coupled to MMAE. While anti-ICOS-53.3 and anti-ICOS-92.17 ADCs had similar efficacy to anti-ICOS-314.8 ADCs on MyLa, anti-ICOS 145.1 ADCs resulted in significantly lower cell death. Finally, all clones showed good ability to act as ADCs with Mab-ZAP, excluding clones 279.1, 145.1 and 121.4.Discussion: ICOS is a promising therapeutic target because it is expressed both by tumor T-cells and regulatory T-cells. We report for the first time the strong and frequent expression of ICOS in CTCLs, as well as the preclinical efficacy of anti-ICOS ADCs on CTCL cell line and PDXs. These results could be extended to the spectrum of follicular variant peripheral T-cell lymphomas.Conclusion: Collectively, our findings provide the preliminary basis for a therapeutic trial [Display omitted] DisclosuresLopez: Emergence Therapeutics: Current holder of individual stocks in a privately-held company. Bagot: Takeda: Membership on an entity's Board of Directors or advisory committees. Olive: ImCheck Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Emergence Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Alderaan Biotechnology: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees.

Updated review on prognostic factors in mycosis fungoides and new skin lymphoma trials.

Ten-year survival rates in mycosis fungoides (MF) broadly varies, however, there is no standardized prognostic index available. This is presumably due to low prevalence, heterogeneity, and diagnostic challenges in MF. Recent studies have focused on identifying objective prognostic indices by using different parameters for survival determinants. The Cutaneous Lymphoma International Prognostic Index (CLIPI) and the Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) represent prototypical studies that identify prognostic factors, seeking to improve management and outcomes in early-stage MF. Detecting these factors and stratifying MF patients according to their disease progression risk may help to manage these patients more efficiently. Review the current literature to determine the risk factors determining prognosis in MF. A Comprehensive literature search was performed using electronic online databases "PubMed" and "Google Scholar" using key words 'prognostic factor', 'prognostic indicator', 'mycosis fungoides', 'Sezary syndrome', 'Skin Lymphoma', 'Cutaneous Lymphoma'. Articles published in English language were considered for the review. The strongest prognostic factor in MF patients is the stage of the disease. T stage and the presence of extracutaneous disease are the most important factors for survival. Other factors that are associated with worse prognosis are male gender, age >60, presence of plaques, folliculotropism, eosinophilia and lymph node stage above N1/Nx. Elevated LDH was associated with later tumor stages and large cell phenotype at diagnosis had a better prognosis. KIR3DL2 was associated with malignant transformation. The PROCLIPI study has assessed risk factors collected in MF patients from different countries and across different ethnicities following a rigorous clinicopathologic process. The findings presented here illustrated that disease prognosis in early stages depends on many contributing factors. Detection and stratification of such factors may allow a personalized approach to management of these patients.