Phenotypical Markers, Molecular Mutations, and Immune Microenvironment as Targets for New Treatments in Patients with Mycosis Fungoides and/or Sézary Syndrome

Primary cutaneous lymphomas encompass a wide spectrum of rare lymphoproliferative disorders originating in the skin, among which, mycosis fungoides (MF) is most common subtype. The treatment this disease based on skin-directed therapies eventually association with biologic response modifiers early phases, whereas patients advanced stages, several therapeutic strategies can be used including mono and/or polychemotherapy and bone marrow transplantation. In recent years, identification specific markers (phenotypical, immunological, molecular) has led to development studies (including two randomized phase III trials). results these are modifying our strategy toward personalized approach which clinical characteristics tumor-node-metastasis-blood stage considered together expression (i.e., CD30-positive for use brentuximab vedotin). This review will provide comprehensive scenario main phenotypical, molecular, immunological related MF pathogenesis evolution, could represent target innovative effective treatments disease. T-cell (CTCLs) skin. Among them, (MF), subtype (Campbell et al., 2010Campbell J.J. Clark R.A. Watanabe R. Kupper T.S. Sezary syndrome arise from distinct subsets: rationale their behaviors.Blood. 2010; 116: 767-771Crossref PubMed Scopus (281) Google Scholar; Quaglino 2012Quaglino P. Pimpinelli N. Berti E. Calzavara-Pinton Alfonso Lombardo G. Rupoli S. al.Time course, pathways, long-term hazards risk trends progression classic fungoides: multicenter, retrospective follow-up study Italian Group Cutaneous Lymphomas.Cancer. 2012; 118: 5830-5839Crossref (63) Scarisbrick 2019Scarisbrick Prince H.M. Papadavid Hodak Bagot M. al.The PROCLIPI international registry early-stage identifies substantial diagnostic delay patients.Br J Dermatol. 2019; 181: 350-357Crossref (31) Willemze 2019Willemze Cerroni L. Kempf W. Facchetti F. Swerdlow S.H. 2018 update WHO-EORTC classification primary [published correction appears Blood 2019;134:1112].Blood. 133: 1703-1714Crossref (0) Scholar), an indolent CTCL clinically characterized by long-standing, scaly, patch lesions preferentially involving buttocks body areas infrequently exposed sunlight (bathing trunk) slow evolution over years patches plaques (early stage) tumors or erythroderma (advanced stage). Lymph node visceral involvement, as well large cell transformation, usually occur late stages (Pimpinelli 2005Pimpinelli Olsen E.A. Santucci Vonderheid Haeffner A.C. Stevens al.Defining fungoides.J Am Acad 2005; 53: 1053-1063Abstract Full Text PDF (339) Scholar) (Figure 1). Sézary (SS) erythrodermic leukemic variant spectrum. phenotypical features molecular mutations, characterize each tumor type growth spreading, have been identified. 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Indeed, adverse events grades 1–2 edema (27%) asthenia fatigue (20%). activity, treatment-induced significant RRs is, response, 42.9% 55.9%, respectively, 13.8 months. series multiple (Abraham 2011Abraham R.M. Zhang Q. Odum Wasik M.A. Biol Ther. 12: 1019-1022Crossref 2018Horwitz Koch Oki Moskowitz Perez al.Activity PI3K-?,? duvelisib preclinical models 131: 888-898Crossref (82) Krejsgaard 2006Krejsgaard Vetter-Kauczok C.S. Woetmann Lovato Labuda Eriksen K.W. al.Jak3- JNK-dependent vascular endothelial factor lymphoma.Leukemia. 1759-1766Crossref (88) Scholar); majority directed them stages. Taken together, heterogeneous landscape number genetic alterations summarized Table 1. Molecular mutations more pathways epigenetic chromatin regulation, TCR T-cell/ signaling, Jak/signal transducer activator transcription (STAT), phosphoinositide 3-kinases (PI3K)/protein kinase (Akt) NF-?B pathway. Nearly all TP53. Less affected represented MAPK NOTCH pathway.Table 1Summary Main Somatic Mutations Reported Genomic Studies CTCLs, Divided Functional Role Pathway BelongingsSomatic MutationsEpigenetic regulationDNMT3A, ASLX3, TET1-3 (Woollard 2016Woollard W.J. Pullabhatla Lorenc Patel V.M. Butler Bayega al.Candidate driver genes genome DNA repair syndrome.Blood. 127: 3387-3397Crossref Scholar)MLL2, SETD1A, RNF20 (McGirt 2015McGirt L.Y. Jia Baerenwald D.A. Duszynski R.J. Dahlman K.B. Zic al.Whole-genome sequencing reveals oncogenic fungoides.Blood. 126: 508-519Crossref (113) Scholar)BCOR, KDM6A, SMARCB1, TRRA