Early-stage Mycosis Fungoides Research Articles

New systemic treatment options in mycosis fungoides and Sézary syndrome

SummaryCutaneous T cell lymphomas (CTCL) are a heterogeneous group of rare non-Hodgkin lymphomas. The most common type of CTCL is Mycosis fungoides (MF). Much less common but clinically and histopathologically related to MF is Sézary syndrome (SS). CTCL are incurable and associated with a reduced quality of life. While early stage MF has a good prognosis and is usually treated with skin directed therapies, advanced-stages require systemic therapies, including retinoids, interferon, cytotoxic chemotherapeutic drugs, low-dose methotrexate, histone deacetylase inhibitors and alemtuzumab. However, relapses are frequent and long-term remissions are achieved only in few cases, e.g. with allogenic stem cell transplantation. In recent years, new therapeutic options have evolved by the approval of brentuximab vedotin and mogamulizumab. Both recently approved therapies demonstrated superiority with regard to overall response rate and progression free survival over traditional systemic therapies. Other promising treatments such as lacutamab and PD-1/L-1 inhibitors are in the pipeline, and more therapeutic agents are currently investigated in clinical trials.

Effect of expression of ICOS in cutaneous T-cell lymphoma and its targeting on killing of malignant cells.

e20040 Background: Advanced stage cutaneous T-cell lymphomas (CTCLs) remain an unmet medical need. Immunomodulatory agents such as mogamulizumab, anti-KIR3DL2 and brentuximab vedotin (BV), an anti-CD30 antibody–drug conjugate (ADC) coupled to monomethyl-auristatin-E (MMAE), 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. 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 monoclonal antibodies with MMAE, in comparison to BV. We used ICOS+ CTCL cell lines (MyLa and MJ), murine xenograft models with MyLa and ICOS+ Patient Derived Xenografts (PDXs) from patients with SS and angioimmunoblastic T-cell lymphoma (AITL). 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 the 5 patients with node involvement. 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 ADCs. In a mouse xenograft model (MyLa), anti-ICOS 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 ADCs significantly improved OS, and reduced the number of tumor cells in the blood, bone marrow and spleen. No evidence of ADC toxicity was observed in treated mice. Conclusions: All together our results show that ICOS is a therapeutic target of interest in CTCLs and provide the preliminary basis for a therapeutic trial

Response to topical corticosteroid monotherapy in mycosis fungoides

Topical corticosteroids alone or in combination with other therapies are widely used to treat mycosis fungoides (MF), but data on response rates to their use as monotherapy in MF are limited. To evaluate the efficacy of topical corticosteroid monotherapy in MF; compare sex, age, stage distributions, and histopathologic features between responders and nonresponders. A retrospective cross-sectional review of patients with MF from 2013 to 2019 treated at Thomas Jefferson University was conducted. Patients with biopsy-proven MF, all stages, who received topical corticosteroid monotherapy were included. Response rates were determined by percent change in body surface area (BSA) involvement and modified Severity-Weighted Assessment Tool (mSWAT). Of the 163 patients with MF in our database, 23% (37/163) initially received topical steroid monotherapy. Of these, 73% (27/37) improved, with an average 65% decrease in BSA (67% in mSWAT); 27% (10/37) did not respond/progressed, with an average 51.6% increase in BSA (57% in mSWAT); and 33% (12/37) had a complete response (BSA, 0%) with prolonged topical steroid use. Early-stage MF and female sex were more represented in responders. Single-center retrospective design. Topical steroid monotherapy in early-stage MF can produce measurable improvements in BSA and mSWAT scores and achieve complete remission in a limited subset of patients.

反射性共聚焦显微镜对早期蕈样肉芽肿定位诊断与疗效监测的研究

反射性共聚焦显微镜对早期蕈样肉芽肿定位诊断与疗效监测的研究

Validation of an algorithm based on clinical, histopathological and immunohistochemical data for the diagnosis of early-stage mycosis fungoides

BackgroundDiagnosis of mycosis fungoides is challenging due to the non-specificity of clinical and histopathological findings. The literature indicates an average delay of 4–6 years for a conclusive diagnosis. Refinement of the histopathological criteria for the diagnosis of patients in early stages of the disease is considered of interest. ObjectivesTo study the histopathological aspects of early-stage mycosis fungoides and the applicability, in a retrospective form, of the diagnostic algorithm proposed by Pimpinelli et al. MethodsObservational, retrospective, transversal study based on revision of histopathological exams of patients with suspected mycosis fungoides. Medical records were reviewed, and complementary immunohistochemistry performed. ResultsSixty-seven patients were included. The most frequent histopathological features were superficial perivascular lymphoid infiltrate (71.6%), epidermotropism (68.7%), lymphocytic atypia (63.8%), hyperkeratosis (62.7%) and acanthosis (62.7%). Forty-three patients scored 4 points at the algorithm, by clinical and histological evaluation. Immunohistochemistry was performed on 23 of the 24 patients with less than 4 points. Of those 23, 22 scored 1 point, allowing a total of 61 patients (91%) with the diagnosis of early-stage mycosis fungoides. Study limitationsIts retrospective character, reduced sample size and incomplete application of the algorithm. ConclusionsApplication of the Pimpinelli et al. algorithm, even in an incomplete form, increased the percentage of cases diagnosed as mycosis fungoides. Routine application of the algorithm may contribute to earlier and specific management and improvement of the patients’ outcome.

Effects of Narrow-band UVB Alone and in Combination with Isotretinoin on Apoptosis and Its Clinical Implications in Early Stage Mycosis Fungoides

Effects of Narrow-band UVB Alone and in Combination with Isotretinoin on Apoptosis and Its Clinical Implications in Early Stage Mycosis Fungoides

Skindex-29 scores indicate poor quality of life in early stage mycosis fungoides

BackgroundQuestionnaire tools are increasingly being used to assess health related quality of life (HRQOL) in mycosis fungoides (MF) patients. However, a thorough understanding of the factors that lead to poor HRQoL in early stage disease and their distribution across patient subgroups is lacking. ObjectivesTo characterize factors affecting HRQoL as assessed by Skindex-29 in subgroups of patients with early stage MF seen at a multidisciplinary cutaneous lymphoma clinic. MethodsSkindex-29, a multidimensional survey that evaluates HRQoL (emotions, symptoms, function), was distributed to early stage MF patients. Overall and component scores were analyzed in three groups: no evidence of disease (NED), active disease with limited early stage (AD-T1), and active disease with more extensive early stage (AD-T2). Scores were also compared among patients receiving different treatment modalities. Results56 patients (9 NED, 36 AD-T1, and 11 AD-T2) were enrolled in the study. Overall Skindex-29 scores and scores for individual dimensions were comparable among the three sub-groups. Similarly, these scores did not significantly differ among treatment groups or after removal of patients with previous staging higher than IB. Analysis of individual questions revealed that NED patients reported higher scores for questions pertaining to anger and fatigue. ConclusionsEarly stage MF patients enrolled in this study had high overall Skindex-29 scores. Surprisingly, Skindex-29 scores of NED patients were comparable to those of patients with active disease, T1 and T2, mostly due to anger and fatigue. Even when skin involvement is minimal or absent, MF patients continue to report impaired HRQoL.

Cost of early-stage mycosis fungoides treatments in Spain.

AimTo identify the most common therapeutic options for the treatment of early-stage mycosis fungoides in Spain, quantify their associated healthcare resource use and costs.MethodsAfter reviewing the literature, a panel of 6 Spanish clinical dermatologists validated the treatments and healthcare resource use through a structured questionnaire. Individual responses were collected, analyzed and presented into a face-to-face meeting in order to reach a consensus. Cost categories considered were: drug acquisition and administration, photo/radiotherapy session and maintenance, clinical follow-up visits and laboratory tests. Costs were expressed in euros from 2018. The Spanish National Health System perspective was considered, taking into account direct health costs and time horizons of 1, 3 and 6 months.ResultsCosts for the skin-directed treatments (SDT) assessed at 1, 3 and 6 months, were: Topical carmustine [€6,593.36, €19,780.09 and €27,592.78]; Phototherapy with psoralens and ultraviolet A light (PUVA) [€1,098.68, €2,999.99 and €3,187.60]; Narrow-band ultraviolet B phototherapy [€1,657.47, €4,842.10 and €4,842.10]; Total skin electron beam therapy (TSEBT) [€6,796.45, €7,913.34 and €7,913.34]. Cost for topical corticosteroids, being considered an adjuvant option, were €17.16, €51.49 and €102.97. Costs for the assessed systemic treatments alone or in combination with SDT at 1, 3 and 6 months, were: Systemic retinoids [€2,026.03, €5,206.63 and €7,426.42]; Systemic retinoids + PUVA phototherapy [€3,066.50, €8,271.26 and €10,046.58]; Interferon alfa + PUVA phototherapy [€1,541.09, €5,167.57 and €6,404.55].ConclusionAccording to the Spanish clinical practice, phototherapies in monotherapy were the treatments with the lowest associated costs regardless of the time horizon considered. TSEBT turned out as the treatment with the highest associated costs when considering 1 month. However, while considering 3 and 6 months the treatment with the highest associated costs was topical carmustine. The results of this analysis may provide critical information to measure the disease burden, to detect unmet medical needs and to advocate towards better treatments for this rare disease.

Survival in Mycosis Fungoides and Sezary Syndrome: How Can We Predict Outcome?

Early-stage mycosis fungoides (MF) has been associated with long survival. A recent meta-analysis including 6,279 patients with MF and Sezary syndrome found that about 10-20% of stage IB patients don't survive 5 years, whereas patients with advanced-stage MF and Sezary syndrome have a 5-year survival chance of about 20-60%. Identifying prognostic markers to better identify those at risk of limited survival may allow improved management choices and this, coupled with newer treatments, could improve survival.

Reflectance confocal microscopy may be included as part of the diagnostic algorithm of early-stage mycosis fungoides.

Reflectance confocal microscopy (RCM), a noninvasive, real-time technique of computed tomography, has been widely used for pigmentary, inflammatory, and tumor diseases of the skin. Our main purpose was to analyze the consistency between pathological and RCM characteristics of early-stage mycosis fungoides (MF) and the utility of RCM in the diagnosis of early-stage MF. According to the RCM features of MF in the early stage, the biopsy sites of 40 cases of suspected MF and 20 cases of chronic inflammatory skin diseases clinically were preliminarily located. Histopathologic and immunohistochemical examinations were performed to make a diagnosis based on the diagnostic algorithm proposed by the International Society for Cutaneous Lymphomas. Among the 60 patients observed, there were 12 confirming cases of MF, 14 suspecting cases, 6 not completely excluding cases, and 28 eliminating cases according to the diagnostic algorithm, as well as characteristics of RCM were typical in 8 cases, suspected in 16 cases, not excluded in 3 cases, and excluded in 33 cases. The kappa value was 0.769 (P<.01), which means there is a strong consistency between the classification by RCM and the diagnosis algorithm. MF in patch stage and plaque stage (IA to IIB) has typical characteristics of RCM, respectively. RCM can be used as an objective and convenient auxiliary means to diagnose early-stage MF and may be included as part of the diagnostic algorithm of early-stage MF.

Radiotherapy Eradicates Malignant T Cells and Is Associated with Improved Survival in Early-Stage Mycosis Fungoides.

Mycosis fungoides is the most common subtype of cutaneous T-cell lymphoma. Skin-directed treatments often improve but do not cure mycosis fungoides skin lesions. The purpose of this study was to (i) assess whether remission was associated with malignant T-cell clone depletion at treated sites using either low-dose radiotherapy (LDRT, 8 Gy) or topical steroids and (ii) assess whether a clone-ablative therapy, like LDRT, is associated with overall survival in patients with high-risk early-stage CTCL. Pre- and posttreatment biopsies from 20 lesional skin samples of 18 patients with mycosis fungoides who received either 8 Gy LDRT (n = 16) or topical steroids (n = 4) underwent high-throughput T-cell receptor sequencing of the TCRB gene to quantify the malignant T-cell clone. For the retrospective chart review, overall survival of 47 high-risk early-stage patients was compared between patients who did or did not receive radiation. LDRT eradicated the clone in 5 of 16 lesions and reduced it >90% in 11 of 16; there were no recurrences in these lesions. Patients treated with topical steroids appeared to clinically improve, but the malignant clone persisted. We found that the number of residual malignant T cells predicted lesion recurrence. A retrospective review showed that early-stage high-risk patients who received radiation as part of their treatment regimen had prolonged overall survival compared with patients who did not. These findings demonstrate that LDRT can eradicate malignant T cells in mycosis fungoides, provides robust disease control, and is associated with improved survival in high-risk early-stage patients.

REACH: Study to Determine the Aetiology of Chlormethine Gel Induced-skin Drug Reaction in Early Stage Mycosis Fungoides Cutaneous T Cell Lymphoma (MF-CTCL)

REACH: Study to Determine the Aetiology of Chlormethine Gel Induced-skin Drug Reaction in Early Stage Mycosis Fungoides Cutaneous T Cell Lymphoma (MF-CTCL)

Stage-dependent Increase in Expression of miR-155 and Ki-67 and Number of Tumour-associated Inflammatory Cells in Folliculotropic Mycosis Fungoides.

Recent studies suggest that folliculotropic mycosis fungoides (FMF), the most common variant of mycosis fungoides (MF), presents with 2 distinct clinicopathological stages: early indolent stage and more aggressive advanced/tumour stage. To further characterize these stages, miR-155 expression was studied with qRT-PCR and found to be significantly higher in biopsies of tumour-stage FMF compared with early-stage FMF and inflammatory dermatoses. There was no statistically significant difference in miR-155 expression between early-stage FMF and early-stage MF, nor between tumour-stage FMF and tumour-stage MF. Immunohistochemical analysis revealed a significantly increased number of dermal Ki-67+ proliferating lymphocytes in tumour-stage FMF, together with an increased number of CD20+ B cells and CD68+ macrophages compared with early-stage FMF. Thus, similar to classic MF, miR-155, Ki-67 tumour cell immunoreactivity, and certain tumour-infiltrating inflammatory cells are differentially expressed in early-vs tumour-stage FMF. The results of this study corroborate the notion that FMF presents with 2 distinct stages.

The Course of Mycosis Fungoides under Cytokine Pathway Blockers: A Multicentre Analysis of Real-Life Clinical Data

Literature regarding the effect of biologics on the course of mycosis fungoides (MF) is scarce. This multicentre study analysed retrospective data on 19 patients with MF, who were treated with biologics; 12 for inflammatory conditions coexisting with MF, and 7 for MF misdiagnosed as an inflammatory skin disease. Eight patients were treated with anti-tumour necrosis factor-α-monotherapy; 6 had early-stage MF, in 3 patients MF preceded and in 3 MF was diagnosed after initiation of biologics, with no stage-progression or with stable disease, respectively (median treatment time concurrent with MF 57 months). Two patients had advanced stage MF: IIB, treated for 15 months with no stage-progression, and IVA1, treated for 8 months, died of disease 10 months later. The other 11/19 patients received anti-interleukin-17A and/or antiinterleukin-12/23 or anti-interleukin-23 (with/without anti-tumour necrosis factor-α/anti-interleukin-4/13), with stageprogression in 8 patients after a median of 8 months’ treatment. Although, in general, biologics should be avoided in patients with MF, these results indicate that anti-tumour necrosis factor-α-monotherapy might not aggravate the disease course in early-stage patients. Interleukin-17A, interleukin-12/23 and interleukin-23 pathway-blockers may prompt progression of MF.

MicroRNA-106b Regulates Expression of the Tumour Suppressors p21 and TXNIP and Promotes Tumour Cell Proliferation in Mycosis Fungoides.

A prognostic 3-miRNA classifier for early-stage mycosis fungoides has been developed recently, with miR-106b providing the strongest prognostic power. The aim of this study was to investigate the molecular function of miR-106b in mycosis fungoides disease progression. The cellular localization of miR-106b in mycosis fungoides skin biopsies was determined by in situ hybridization. The regulatory role of miR-106b was assessed by transient miR-106b inhibitor/mimic transfection of 2 mycosis fungoides derived cell lines, followed by quantitative real-time PCR (RT-qPCR), western blotting and a proliferation assay. MiR-106b was found to be expressed by dermal T-lymphocytes in mycosis fungoides skin lesions, and miR-106b expression increased with advancing mycosis fungoides stage. Transfection of miR-106b in 2 mycosis fungoides derived cell lines showed that miR-106b represses the tumour suppressors cyclin-dependent kinase inhibitor 1 (p21) and thioredoxin-interacting protein (TXNIP) and promotes mycosis fungoides tumour cell proliferation. In conclusion, these results substantiate that miR-106b has both a functional and prognostic role in progression of mycosis fungoides.

Early-stage Mycosis Fungoides: Epidemiology and Prognosis.

Most patients with mycosis fungoides are diagnosed with early-stage disease. However, prevalence of early-stage disease is unknown, and evidence of its burden is scarce. The aim of this study is to estimate the prevalence of early-stage mycosis fungoides, how long patients live with early-stage disease and to characterise these patients. Data were obtained from 4 key publications and from US cancer registries (Surveillance, Epidemiology and End Results Program; SEER). The derived incidence of early-stage mycosis fungoides was 0.26/100,000 (UK), 0.29/100,000 (US) and 0.38/100,000 (US-SEER) and the prevalence was 4.8/100,000 (UK), 5.2/100,000 (US) and 6.6/100,000 (US-SEER). Early-stage disease may last for 18 years. From SEER registries, 3,132 were diagnosed at early stage (mostly stage IA). Median age at diagnosis was 58 years. Compared with stage IA, the relative risk of death was 1.3 for stage IB and 3.5 for stage IIA. We confirm the rarity of early-stage mycosis fungoides, a differential prognosis and the potential for elevated burden of disease.

Mycosis Fungoides and Variants of Mycosis Fungoides: A Retrospective Study of 93 Patients in a Chinese Population at a Single Center

BackgroundMycosis fungoides (MF) is the most common types of cutaneous T cell lymphoma. It typically presents with erythematous patches and plaques in the early stage and tumors and extracutaneous involvement with possibly fatal outcomes in the late stage. To facilitate early and accurate diagnosis of MF, it is essential to be knowledgeable of classic and variants of this disease. However, there is limited published data in the Chinese population.ObjectiveTo characterize our patient group and to provide additional insight into these malignancies.MethodsPatients diagnosed with mycosis fungoides and its variants from October 2012 to January 2018 were retrospectively analyzed. Disease-specific survival (DSS) rate and curve according to early and advanced stages were also calculated.ResultsThe mean age at diagnosis of ninety-three MF patients was 38.9±1.73 years (range: 6~77). Forty-five males (48.4%) and 48 females (51.6 %) were included in this study. The DSS rate of early-stage MF was 98.6%, while that of advanced stage MF was 88.9%. There was a significant difference in DSS rate between early stage and advanced stage MF (p=00.042, log-rank test). The median age of 10 patients with hypopigmented MF (hMF) was 10.5 years (range: 6~28). The age of hMF was younger than that of classical MF patients (p<0.05).ConclusionEarly-stage MF has a better prognosis than advanced stage and hMF affects younger people than classic MF among Chinese. This study provides an insight into mycosis fungoides and its variants in a Chinese population.

Phototherapy of mycosis fungoides

Currently, phototherapy has been widely used in the treatment of various skin diseases, including mycosis fungoides. The article provides a literature review on the use of various spectra ultraviolet therapy in the treatment of patients with early stages of mycosis fungoides. The mechanisms of action of medium-wave ultraviolet therapy (UVB-311 nm) and PUVA therapy, causing the immunosuppressive, anti-inflammatory and anti-proliferative effect, are described. The results of retrospective studies of PUVA therapy and UVB-311 nm efficacy in patients with cutaneous T-cell lymphoma are presented, as well as modern literature evidence of the need for standardization of phototherapy methods for patients with mycosis fungoides.

The different faces of mycosis fungoides: results of a single-center study.

Mycosis fungoides (MF) accounts for the majority of cutaneous lymphomas. Apart from the predominant Alibert-Bazin type, several clinicopathological variants of diverse prevalence and biological behavior have been described. Data on clinical and epidemiological aspects of MF clinical subtypes are still weak. To outline the clinical and epidemiological profile of the different MF types in a large volume of Greek patients. Retrospective analysis of 688 MF cases treated in our lymphoma clinic. Epidemiological, clinical, pathological, and immunohistochemical data were retrieved. Six-hundred and thirty-six patients (416 males, 220 females) were included. The mean age at diagnosis was 60.2years; the mean duration of disease prior to diagnosis was 63.2months. Early-stage MF (I-IIA) involved 475 cases (74.7%). The prevalent type was classical MF (68.5%), followed by folliculotropic (17%), poikilodermic (5.5%), and psoriasiform (4.7%) MF. Atypical MF lesions as the sole manifestation of folliculotropic mycosis fungoides (FMF) - alopecia areata-like lesions (n=10), keratosis pilaris-like lesions (n=9) or acneiform rash (n=4) - were also observed. Both poikilodermic and folliculotropic subtypes mainly involved younger patients. A significant diagnostic latency concerning poikilodermic and psoriasiform MF cases was recorded. Only 23 (3.3%) cases were of juvenile onset, with classical and poikilodermic MF equally affecting this age group, closely followed by FMF. Our study presents the whole clinical-epidemiological spectrum of MF in a large Greek cohort. The high prevalence of atypical MF manifestations characterized by early onset and indolent clinical course stood out among our FMF sample.

Mycosis fungoides in pediatric patients: Clinical features, diagnostic challenges, and advances in therapeutic management.

Mycosis fungoides (MF) is the most common primary cutaneous lymphoma in pediatric patients. Given the indolent nature of MF, symptoms often present in childhood but may not be diagnosed as MF until adulthood. Delayed diagnosis is associated with poor long-term prognosis. Thus, increased clinician recognition and accurate diagnosis of early-stage MF in pediatric patients is critically important. In this review, we summarize the clinical features of the most common pediatric MF subtypes and highlight important differences between pediatric and adult MF. Moreover, we reviewed all pediatric MF case series published between 2008 and 2018 to analyze treatment modalities and identify emerging therapies. As treatment of pediatric MF is complex, selection of therapy varies significantly depending upon the specific clinical characteristics, disease severity, and patients' preferences.