Long-term Assessment of Chlormethine Gel in Mycosis Fungoides

Primary cutaneous lymphomas (PCLs) are a rare group of lymphoproliferative disorders with neoplastic lymphocyte proliferation in the skin. Cutaneous T-cell lymphomas (CTCL) make up 75% of PCLs, with mycosis fungoides (MF) being the most common. The cause of MF is unclear, but persistent antigenic stimulation and chronic inflammation may lead to neoplastic transformation. Pathogenesis involves genetic and epigenetic abnormalities, with a crucial role played by the skin microenvironment. Data from the International PROCLIPI registry (PROspective Cutaneous Lymphoma International Prognostic Index Validation and Evaluation) provide insight into the clinical management and outcomes of CTCL. This study has confirmed that early-stage disease has a relatively favorable prognosis, with a 5-year survival rate of about 90% for stage IA patients. Treatment is stage-dependent. Early stages are managed with skin-directed therapies (topical steroids, chlormethine and phototherapy) as first lines, while refractory or advanced disease requires systemic therapies such as interferon, bexarotene, and extracorporeal photopheresis. Chemotherapy and new monoclonal agents are used for refractory advanced cases. Topical chlormethine (TC) is an alkylating agent successfully used in treating CTCL since the 1950s. It works by a cytotoxic mechanism on DNA, altering the growth of neoplastic cells and enhancing the host's immunogenic potential. Initially, TC was packaged in an aqueous solution, but its use was limited by a high rate of skin hypersensitivity. In 2013, a multicenter, randomized, blinded phase II study compared 0.02% TC ointment with 0.02% TC gel, demonstrating the gel's non-inferiority to the ointment. The study also recorded longer and faster responses in the gel arm. No detectable systemic absorption of the drug was observed in patients' blood, consistent with previous case series. The evidence on the development of secondary neoplasms is controversial, particularly the risk of non-melanoma skin cancers (NMSC), which ranges from 0 to 9%. This risk is higher in patients previously treated with other modalities known to increase skin cancer incidence (e.g., radiotherapy and phototherapy). Melanoma development was reported by Ramsay et al. in a single patient with Fitzpatrick type I skin and a history of NMSC.

Real-world data from numerous studies have confirmed the efficacy of TC gel in treating early-stage MF and its use in combination with systemic therapies for advanced stages. In particular, the PROVE study, based on US real-world experience, demonstrated that modulating the TC schedule to every other day maintained good efficacy while reducing the incidence of adverse events, such as irritant contact dermatitis (ICD), and improving patient compliance. In a previous retrospective study on the first patients treated with TC gel in Italy, was showed that hyperpigmentation correlates with good response.

Currently, there is a lack of data on long-term response, recurrence rates after initial response, and the effect on treated areas considering the significant irritative response.

• Percentage of CR and ORR (CR+PR) [Time frame: Up to 12 months]
• Nelson-Aalen estimation [Time frame: Up to 12 months]
• Kaplan-Meier estimation of Time to recurrence (TTR) [Time frame: Up to 12 months]
• Percentage of relevant toxicities over an extended use [Time frame: Up to 12 months]
• Percentages of toxicity in specific areas [Time frame: Up to 12 months]
• Percentages of skin toxicity by patient characteristics [Time frame: Up to 12 months]
• Frequency of use of different regimens [Time frame: Up to 12 months]