Background

Mycosis fungoides (MF) has long been treated with topical mechlorethamine hydrochloride (MCH), but reports on skin tissue changes over the course of treatment are still lacking.

Objective

To prospectively analyze the histopathologic and molecular skin responses to MCH gel-based monotherapy in MF patients and identify potential correlations predicting long-term clinical outcomes.

Methods

This was a single-center, paired biopsy cohort study designed to evaluate the histopathologic, immunophenotypic, and molecular profiles of MF skin lesions before and after 4-6 weeks of daily applications of MCH 0.02% gel. Follow-up data on clinical response (CR) and safety outcomes beyond a 1-year period were also retrieved. Co-primary endpoints were histopathologic changes from baseline to week 4-6 of treatment, and potential correlations between clinical, histopathologic, and molecular skin responses.

Results

Of 13 patients (12 males; mean ± SD age 53.6 ± 20.2) included, the majority (84.6%) had early-stage disease (≤ IIA) at MCH initiation. Classical MF was the prevalent type (61.5%). Median follow-up was 14 months (range 8-17). Following MCH monotherapy, skin biopsy specimens of treated MF lesions showed that all cases with epidermotropic features (10/13; 77%) displayed loss (5/10; all sustained complete CR) or lower degrees (5/10) of initial epidermotropism. Only 1 of 4 folliculotropic MF (FMF) cases showed no signs of follicular infiltration. Dermal infiltrate density decreased in most (69.2%) patients to no/low and moderate in 6 (46.2%) and 3 (23%) cases, respectively, while it remained unchanged in 4 (30.8%) cases. Notably, loss of CD30 expression after MCH application was detected in 1 FMF patient. TCRγ-targeted PCR turned negative in 5 of 9 initially positive lesional sites (4 sustained complete CR). With respect to CR, 12/13 (92.3%) patients achieved a complete (n=1) or partial (n=11) skin clearance after 1 month of treatment, while nearly 77% (10/13) were responsive to MCH at 9 months. Overall response rate at 12 months was 61.5% (8/13); 1 patient maintained a prolonged stable disease and 4 developed progressive disease. No critical safety concerns were reported. MCH-induced contact dermatitis occurred in 10/13 (77%) subjects, including 1 case of pseudotumor formation. Treatment was discontinued in 2 cases due to drug-related cutaneous intolerance.

Conclusions

This is the first to our knowledge study focusing on the histopathologic and molecular aspects of MF patients treated with MCH 0.02% gel monotherapy. Our results suggest that histological and molecular skin responses can occur early in the course of treatment, facilitating clinical response evaluation, especially in patients with local dermatitis reactions. The potential benefits of topically applied MCH for advanced and/or folliculotropic MF forms warrant further investigation.