CC: Writing review and editing

CC: Writing review and editing. == Funding Statement == The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article. == Conflict of interest == JR reports the following: research funding: Merck, Corvus Pharmaceuticals, Kymera Therapeutics; consulting: Acrotech biopharma, Kyowa Kirin. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. == Publishers note == All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. sites with indolent behavior. In advanced disease, there can be involvement of lymph nodes, blood, and/or visceral organs. Szary syndrome (SS) is an aggressive form of CTCL that typically presents with erythroderma (erythema and scale affecting >80% of body surface area), lymphadenopathy, and leukemic blood involvement (13). The exact pathogenesis of MF/SS is not known, but several molecular and immunologic elements have been implicated BAX in their progression, presenting potential targets for therapy. We discuss how recent advances in the understanding of the pathophysiologic mechanisms of CTCL allow for increased applications of current and novel treatments, including monoclonal antibodies, immune checkpoint inhibitors, and Janus kinus pathway inhibitors in advanced MF/SS. == Monoclonal antibodies == Monoclonal antibodies are immunoglobulins that target epitopes or antigens and are utilized as immunomodulatory and cytokine-targeting agents for conditions including rheumatoid arthritis, multiple sclerosis, and psoriasis (4). In CTCL, CD52, C-C chemokine receptor 4 (CCR4), CD30, and CD25 have been exploited as therapeutic targets (5). == Alemtuzumab == Alemtuzumab is an anti-CD52 monoclonal antibody that was initially approved by the FDA in 2001 for B-cell chronic lymphocytic leukemia (B-CLL) (6). CD52 is a small glycopeptide expressed on the cell surface of normal and malignant T lymphocytes, along with other leukocytes (7).Elevated CD52 expression on CD4+T lymphocytes, the main circulating cell in SS, makes this molecule an applicable target (8). Alemtuzumab is historically considered the first monoclonal antibody treatment for MF/SS. It first showed promise as a CTCL therapy when a 2002 report showed an overall response rate (ORR) of SKF 86002 Dihydrochloride 100% in 3 cases of CTCL with response duration of up to four years (5,9). Alemtuzumab underwent a phase II clinical trial in 2003 as a potential treatment in advanced MF/SS. The safety and efficacy of the drug was evaluated in 22 patients with SKF 86002 Dihydrochloride advanced MF/SS who failed to respond to standard treatments SKF 86002 Dihydrochloride of psoralen + ultraviolet A phototherapy (PUVA), radiotherapy, or chemotherapy. ORR to alemtuzumab was determined by administering the drug using an escalating dose regimen of 3 mg, 10 mg, and finally target dose of 30 mg, three times weekly for up to 12 weeks (10). The ORR was 55% in the 22 MF/SS patients, with 32% reaching complete remission and 23% having partial remission. The ORR in SS patients (n=7) was 86%. Adverse side effects to treatment included cytomegalovirus reactivation in four patients and suspected or confirmed infections in six patients (3 fever of unknown origin, 1 herpes simplex, 1 fatal aspergillosis, 1 mycobacterium pneumonia.) (10) Despite this, it was determined that alemtuzumab was a potentially safe and viable therapy for advanced MF/SS with the use of antibiotic and antiviral prophylaxis (10). In 2014, a retrospective analysis SKF 86002 Dihydrochloride of 39 patients with advanced CTCL evaluated the long-term safety and efficacy of alemtuzumab treatment for MF/SS. Overall ORR was 51%; however, 62% of patients had grade 3 or higher infections and 26% had hematologic toxicity. For patients with SS, there was an ORR of 70% while in patients with MF, the ORR was only 25%, supporting alemtuzumab as a better treatment option for SS than MF (11). Since then, newer monoclonal antibodies with more favorable side effect profiles have been approved and/or have undergone clinical studies for treatment of MF/SS. == Denileukin diftitox == Denileukin Diftitox (Dd) is a fusion protein combining diphtheria toxin and interleukin-2 (IL-2). Binding of Dd to IL-2 receptors (IL-2R) leads to internalization of the toxin and subsequent cell death (12). Dd was approved for the treatment of relapsed/refractory.