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Mogamulizumab (MOG) is an antibody targeting the CCR4 receptor, authorized for relapsed or refractory peripheral T-cell (PTCL) and cutaneous T-cell lymphomas (CTCL). Its adoption in guidelines and endorsement by FDA and EMA established it as a systemic treatment, especially for advanced disease stages due to its comparatively lower toxicity. Clinical trials and real-world evidence have underscored its efficacy in advanced CTCLs, including mycosis fungoides and Sézary syndrome; PTCLs; and adult T-cell leukemia/lymphoma (ATLL), showcasing positive outcomes. Notably, the drug has demonstrated significant response rates, disease stability, and extended periods of progression-free survival, suggesting its applicability in cases with multiple treatment lines. Its safety profile is generally manageable, with adverse events (AEs) primarily related to the skin, infusion-related reactions, drug eruptions, autoimmune diseases, and skin disorders. The latter seem to appear as CCR4 can promote the skin-specific homing of lymphocytes, and MOG is directed against this receptor. While combination with immunostimulatory agents like interferon alpha and interleukin 12 has shown promising results, caution is urged when combining with PD1 inhibitors due to the heightened risk of immune-mediated AEs. The introduction of MOG as a systemic treatment implies a significant advancement in managing these diseases, supported by its favorable safety profile and complementary mechanisms.

Background: Brentuximab vedotin (BV) has been approved for CD30-expressing cutaneous T-cell lymphoma (CTCL) after at least one previous systemic treatment. However, real clinical practice is still limited., Objectives: To evaluate the response and tolerance of BV in a cohort of patients with CTCL., Methods: We analysed CTCL patients treated with BV from the Spanish Primary Cutaneous Lymphoma Registry (RELCP)., Results: Sixty-seven patients were included. There were 26 females and the mean age at diagnosis was 59 years. Forty-eight were mycosis fungoides (MF), 7 Sézary syndrome (SS) and 12 CD30+ lymphoproliferative disorders (CD30 LPD). Mean follow-up was 18 months. Thirty patients (45%) showed at least 10% of CD30+ cells among the total lymphocytic infiltrate. The median number of BV infusions received was 7. The overall response rate (ORR) was 67% (63% in MF, 71% in SS and 84% in CD30 LPD). Ten of 14 patients with folliculotropic MF (FMF) achieved complete or partial response (ORR 71%). The median time to response was 2.8 months. During follow-up, 36 cases (54%) experienced cutaneous relapse or progression. The median progression free survival (PFS) was 10.3 months. The most frequent adverse event was peripheral neuropathy (PN) (57%), in most patients (85%), grades 1 or 2., Conclusions: These results confirm the efficacy and safety of BV in patients with advanced-stage MF, and CD30 LPD. In addition, patients with FMF and SS also showed a favourable response. Our data suggest that BV retreatment is effective in a proportion of cases., (© 2022 European Academy of Dermatology and Venereology.)

Deregulation of JAK-STAT pathway seems to be relevant in mycosis fungoides (MFs). We report the case of a 23-year-old woman diagnosed of atypical MF carrying isolated PCM1::JAK2 fusion and eosinophilia. The disease was refractory to common treatments and progressed increasing the number of large CD30 positive T-cells. After progression, treatment with brentuximab vedotin was decided and decreased the proportion of large cells, but the low-grade component persisted, and the skin lesions worsened. Immunohistochemical expression of p-STAT3 detected in most tumor cells demonstrated the abnormal activation of JAK-STAT pathway. Very few cases of mature T-cell lymphomas carrying PCM1::JAK2 gene fusion have been reported to date, and we review previous cases described with this alteration. Described cases shared similar clinicopathological features and low genetic complexity, and the presence of PCM1::JAK2 fusion associates with a distinctive form of the disease., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: 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., Methods: 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., Findings: 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., Interpretation: 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., Funding: Instituto de Salud Carlos III and the European Regional Development Fund., Translation: For the Spanish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests PLO-R reports advisory board honoraria from Takeda, Kyowa, 4SC, MIRAGEN, Helsinn, Recordati Rare Diseases, and Innate Pharma. CM reports advisory board honoraria from Kyowa and Takeda. TE reports advisory board honoraria from Takeda. OS reports advisory board honoraria from Takeda, Eisai, Kyowa-Kirim, and Ferrer Pharma. FG reports speaker fees from Takeda. OS reports consulting, advisory, and advisory board honoraria from Roche, ISDIN, and Sanofi. MAPP reports advisory board honoraria, lecture fees, and research funding from Millenium Pharmaceuticals (now Takeda Oncology); advisory board honoraria and research funding from Gilead; advisory board honoraria and lecture fees from Jansen; advisory board honoraria from Celgene, Nanostring, and Kyowa Kirin; and research funding from Kura. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

CD30 + primary cutaneous lymphomas comprise a large group of malignant lymphoproliferative disorders that present in the skin without extracutaneous involvement at the time of diagnosis. The incidence of these lymphomas is low, at 7 to 10 cases per 100 000 population. Two types, derived from T cells (70%-85%) or B cells (15%-30%), have been identified. Hematologists and oncologists have increasingly recognized the idiosyncrasy of primary cutaneous lymphomas, as reflected in the updated classification of the World Health Organization. However, there remain nuances or small differences to consider when managing these conditions, obliging dermatologists to continue to strive to fully reconcile the various clinical pictures in future reviews of the classification of lymphoid neoplasms. A diagnosis of a primary cutaneous lymphoma is based on clinical, histopathologic, immunophenotypic, and genotypic criteria, particularly evidence of T- or B-cell lymphoid monoclonality in lesions. Also relevant are complementary tests to rule out extracutaneous involvement., (Copyright © 2020 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Primary cutaneous T-cell lymphomas other than mycosis fungoides, Sézary syndrome, and lymphoproliferative CD30 + disorders are few, accounting for less than 5% of all cutaneous lymphomas. A cytotoxic phenotype is characteristic of these tumors, and their clinical behavior is usually aggressive. Patients often present with extracutaneous symptoms or develop them shortly after diagnosis. Management is usually multidisciplinary, and intensive systemic therapy and bone marrow transplantation should be considered. Cutaneous B-cell lymphomas account for approximately 30% of primary cutaneous lymphomas. They make up a heterogeneous group of tumors that have different clinical and pathological features. Clinical course also varies. Presenting as papules, nodules, or tumors of variable reddish-violaceous coloring, the lesions may be solitary or multiple and occasionally form clusters. There may also be generalized lesions, present at multiple sites on the trunk, head, or extremities. Three well-defined groups of primary cutaneous lymphoma have been reported: follicle center lymphoma; marginal zone lymphoma, which follows an indolent course; and a diffuse large B-cell lymphoma, leg type, which follows an aggressive course., (Copyright © 2020 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Notch is a family of transmembrane receptors that participate in the regulation of cell differentiation, proliferation, and stemness. Notch pathway activation has also been found associated with different human cancers including primary cutaneous T-cell lymphomas (CTCL). The elucidation of the mechanisms driving Notch activation in these particular diseases has remained elusive. Here we studied the possibility that DNA methylation at Notch pathway gene promoters and/or deregulation of Notch-associated microRNAs contribute to activate Notch in mycosis fungoides (MF). By genome-wide DNA methylation analysis, we failed to detect any consistent methylation at the Notch1, the Notch-ligand Jagged1, or the Notch-target Hes1 gene promoters, but found a significant methylation of the Notch-related microRNAs, in particular miR-200c and miR-124. Downregulation of miR-200c is associated with overexpression of Jagged1, concomitant to Notch1 activation. CTCL cell lines were infected with lentiviral vector encoding for miR-200c and ectopic expression of miR-200c in CTCL lines resulted in Jagged1 protein downregulation associated with a reduction in the levels of active Notch1. Our study deciphers an epigenetic mechanism regulating the Notch pathway in (MF) that might contribute to the future design of more specific therapeutic strategies.

Mycosis fungoides is the most common form of primary cutaneous T-cell lymphoma. Several clinical and clinicopathological variants of mycosis fungoides have been reported. A 75-year-old woman presenting with multiple ill-defined areas of marked cutaneous wrinkling on the trunk and extremities is reported. Histopathological examination showed characteristic features of mycosis fungoides along with an interstitial dermal infiltrate composed predominantly of atypical lymphocytes with histiocytes intermingled within the collagen bundles. A focal reduction and fragmentation of elastic fibers was demonstrated. This observation illustrates a peculiar and previously unreported clinicopathological presentation of mycosis fungoides: cutis laxa-like mycosis fungoides, expanding the spectrum of mycosis fungoides variants associated with abnormalities of the dermal elastic fibers., (© 2012 Japanese Dermatological Association.)

Chromosomal aberrations involving T-cell receptor (TCR) gene loci have been described in several T-cell malignancies. In primary cutaneous T-cell lymphomas (CTCL), the frequency of these aberrations has not yet been well established. We analyzed TCR gene loci (TCRAD, TCRB, and TCRG) status in CTCLs by fluorescence in situ hybridization (FISH). Twenty-five patients with CTCLs were included in the study: 13 Sézary syndromes (SS), six tumoral stage mycosis fungoides (MFt), and six primary cutaneous anaplastic large cell lymphomas CD30(+) (cALCL-CD30(+)). FISH was performed with three break-apart probes flanking TCRAD (14q11), TCRB (7q34), and TCRG (7p14) loci in each case. TCR gene chromosomal rearrangements were not detected in any of the analyzed cases. Gains of TCRB and TCRG genes were observed in 23% (3 of 13) of SS and 50% (3 of 6) of MFt, reflecting the presence of trisomy and/or tetrasomy of chromosome 7 already detected by conventional cytogenetics and array comparative genetic hybridization techniques. TCR loci rearrangements are not frequent in CTCLs; however, we cannot exclude a pathogenic role in these malignancies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Mycosis fungoide (MF) patients who develop tumors or extracutaneous involvement usually have a poor prognosis with no curative therapy available so far. In the present European Organization for Research and Treatment of Cancer (EORTC) multicenter study, the genomic profile of 41 skin biopsies from tumor stage MF (MFt) was analyzed using a high-resolution oligo-array comparative genomic hybridization platform. Seventy-six percent of cases showed genomic aberrations. The most common imbalances were gains of 7q33.3q35 followed by 17q21.1, 8q24.21, 9q34qter, and 10p14 and losses of 9p21.3 followed by 9q31.2, 17p13.1, 13q14.11, 6q21.3, 10p11.22, 16q23.2, and 16q24.3. Three specific chromosomal regions, 9p21.3, 8q24.21, and 10q26qter, were defined as prognostic markers showing a significant correlation with overall survival (OS) (P=0.042, 0.017, and 0.022, respectively). Moreover, we have established two MFt genomic subgroups distinguishing a stable group (0-5 DNA aberrations) and an unstable group (>5 DNA aberrations), showing that the genomic unstable group had a shorter OS (P=0.05). We therefore conclude that specific chromosomal abnormalities, such as gains of 8q24.21 (MYC) and losses of 9p21.3 (CDKN2A, CDKN2B, and MTAP) and 10q26qter (MGMT and EBF3) may have an important role in prognosis. In addition, we describe the MFt genomic instability profile, which, to our knowledge, has not been reported earlier.

Background: Folliculotropic mycosis fungoides (MF) is a rare variant of cutaneous T-cell lymphoma in which the neoplastic T lymphocytes display tropism for the follicular epithelium., Objectives: To better categorize this rare form of cutaneous T-cell lymphoma we evaluated the clinical, pathological, and immunophenotypic findings, and the response to therapy and course of the disease., Methods: Folliculotropic MF cases were selected from the registry of the Thematic Network of Cutaneous Lymphoma of Barcelona (Spain) from 1988 to 2007., Results: Twenty patients (11 male, 9 female) with a mean age of 54 years were included. Mean follow-up time was 43 months. The most common sites of involvement were the head and neck (80%), upper extremities, and thorax. Infiltrated plaques (55%), acneiform lesions (comedo-like and epidermal cysts) (45%), and follicular keratosis-pilaris-like lesions (45%) were the more prominent features. Histopathological findings included selective infiltration of the follicular epithelium by atypical lymphocytes in all cases. Mucinous degeneration of the follicular epithelium occurred in 60% of cases. Psoralen plus ultraviolet A therapy was the treatment of choice in the majority of patients, but these patients did not respond as well as patients with classic MF. Radiotherapy (local or total skin electron beam) was found to be the most effective treatment. A good response to bexarotene was seen in some patients., Limitation: This was a case series descriptive study., Conclusions: Folliculotropic MF is a rare but well-defined clinicopathological variant of MF. Although refractory to standard therapies used in classic MF, most of our patients showed only slow disease progression., (Copyright 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

The association of mycosis fungoides and a primary cutaneous CD30+ lymphoproliferative disorder has been reported and probably represents different clinical aspects of a unique T-cell monoclonal expansion. In this study, 12 patients (6 men and 6 women) presented with lymphomatoid papulosis and mycosis fungoides. A TCRgamma gene rearrangement study was performed by an automated high-resolution PCR fragment analysis method on skin biopsy specimens taken from the different clinical lesions in each patient. An indolent clinical course was observed in the majority of patients. T-cell clonality was identified in 7 of 12 lymphomatoid papulosis lesions (58%) and in 6 skin biopsies of plaque stage mycosis fungoides (50%). In each individual case, where T-cell clonality was detected, both mycosis fungoides and lymphomatoid papulosis specimens exhibited an identical peak pattern by automated high-resolution PCR fragment analysis, confirming a common clonal origin. Only one case showed a clonal TCRgamma rearrangement from the lymphomatoid papulosis lesion, which could not be demonstrated in the mycosis fungoides specimen. The demonstration of an identical clone seems to confirm that both disorders are different clinical manifestations of a unique T-cell monoclonal proliferation. Our results also seem to confirm that the association of mycosis fungoides with a primary cutaneous CD30+ lymphoproliferative disorder usually carries a favourable prognosis.

We describe a 76-year-old woman who had persistent generalized pruritus as the only cutaneous manifestation of a cutaneous T-cell lymphoma (mycosis fungoides). No cutaneous lesions were observed throughout the patient's course. Skin biopsy specimens obtained from normal-looking pruritic skin revealed a discrete perivascular lymphocytic infiltrate in the upper dermis and focal intraepidermal clusters of atypical lymphoid cells (Pautrier's microabscesses). PCR analysis of TCR-gamma gene disclosed a monoclonal T-cell rearrangement. Sequencing of the PCR monoclonal product identified the J(8)V(2)C(2) TCR gene rearrangement. This observation illustrates the existence of a peculiar and exceedingly rare form of mycosis fungoides characterized only by persistent pruritus unresponsive to several therapeutic approaches. The diagnostic difficulties of this rare variant are stressed.

We describe a 76-year-old woman who presented persistent generalized pruritus as the only cutaneous manifestation of a cutaneous T-cell lymphoma (mycosis fungoides). No cutaneous lesions were observed throughout the patient's course. Skin biopsies obtained from normal-looking pruritic skin revealed a discrete perivascular lymphocytic infiltrate in the upper dermis and focal intraepidermal clusters of atypical lymphoid cells (Pautrier's microabscesses). PCR analysis of TCR-gamma gene disclosed a monoclonal T-cell rearrangement. Sequencing of the PCR monoclonal product identified the J(8)V(2)C(2) TCR gene rearrangement. This observation illustrates the existence of a peculiar and exceedingly rare form of mycosis fungoides characterized only by persistent pruritus unresponsive to several therapeutic approaches. The diagnostic difficulties of this rare variant are stressed.

Polymerase chain reaction (PCR) amplification of T-cell receptor-gamma gene rearrangement was used for molecular staging in a case of primary cutaneous T-cell lymphoma (CTCL) with fatal evolution. Although initial evaluation was negative for systemic involvement, the patient died due to heart failure. Autopsy findings revealed lymphomatous myocardial infiltration, but other tissues and organs examined, including lymph nodes, liver, spleen, lung and bone marrow, appeared to be free of disease. Molecular analysis from frozen samples obtained during the initial evaluation, as well as paraffin-embedded material obtained during autopsy, revealed the presence of clonal rearranged bands in all tissues examined except the bone marrow. Subsequent hybridization of PCR products with a tumour-specific oligoprobe confirmed the PCR results, suggesting widespread dissemination of the lymphomatous process. The use of molecular analysis can add significant information about the extent of disease in patients with CTCL and may be helpful in the establishment of therapeutic options.

Pablo Luis Ortiz-Romero,1 Octavio Servitje,2 María Teresa Estrach,3 Rosa María Izu-Belloso,4 Ricardo Fernández-de-Misa,5 Fernando Gallardo,6 Noemí López-Martínez,7 Alejandro Pérez-Mitru7 1Dermatology Department, Hospital 12 de Octubre, Institute I+12, Medical School, University Complutense, CIBERONC, Madrid, Spain; 2Dermatology Department, Hospital Universitari de Bellvitge, IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain; 3Dermatology Department, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain; 4Dermatology Department, Hospital de Basurto, Bilbao, Spain; 5Department of Dermatology and Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; 6Dermatology Department, Parc de Salut Mar-Hospital del Mar, Barcelona, Spain; 7Oblikue Consulting, Barcelona, SpainCorrespondence: Alejandro Pérez-MitruOblikue Consulting, C/Comte D’urgell, 240, 2-D, Barcelona 08036, SpainTel +34 932 521 377Fax +34 937 379 984Email alejandro.perez@oblikue.comAim: To identify the most common therapeutic options for the treatment of early-stage mycosis fungoides in Spain, quantify their associated healthcare resource use and costs.Methods: After 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.Results: Costs 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].Conclusion: According 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.Keywords: health care costs, health resources, mycosis fungoides, lymphoma, T-cell, cutaneous, surveys and questionnaires, Spain