Enhanced clinical and systemic response with combination radiation therapy and topical imiquimod in mycosis fungoides: A pilot study

Abstract Introduction: Mycosis fungoides (MF), the most prevalent type of cutaneous T-cell lymphoma (CTCL), presents significant therapeutic challenges, particularly due to limited durable systemic responses. Radiation therapy (RT) is a potent, skin-directed treatment for MF lesions, often inducing robust local responses even at low doses. However, systemic or abscopal effects of RT remain rare. Topical imiquimod (IMQ), a toll-like receptor 7 agonist, has demonstrated clinical efficacy as an immunomodulator in early-stage MF. Preclinical evidence suggests IMQ can enhance systemic antitumor immune responses when combined with RT. This study evaluates the clinical safety, efficacy, and potential abscopal effects of combining topical IMQ and RT in patients with MF. Methods We conducted a single-arm pilot study enrolling 12 patients with stage IA–IIB MF at Northwestern Memorial Hospital from July 2023 to April 2025. Participants had stable but active disease (>6 months), failed ≥1 prior standard MF therapy, and possessed ≥4 discrete lesions (≥2 lesions with combined surface area ≥50 cm²). At least 2 treated and 2 untreated index lesions were used for Compositive Assessment of Index Lesion Severity (CAILS) assessment. Participants were instructed to apply IMQ 5% cream to designated treated index lesions 3-5 days/week (based on skin tolerability) for 6 weeks. One week after IMQ initiation, localized RT (total dose: 8 Gy over two fractions) was delivered to the treated lesions. Clinical response was assessed using modified Severity-Weighted Assessment Tool (mSWAT), CAILS, and Numerical Rating Scales (NRS) for pruritus and pain. Skin biopsies, swabs, and tape strips were collected pre- and post-treatment (weeks 0 and 8), and histological assessment was performed by dermatopathologists. Results Cohort included 8 males (67%) and 4 females (33%) (mean 59 years). Disease staging included 2 patients at stage IA, 7 at IB, and 3 at IIB, with 4 cases of folliculotropic MF. Significant clinical improvements were observed, with mSWAT scores substantially decreasing from baseline to week 8 (mean 38.1 to 17.7, p<0.001). Treated and untreated lesions demonstrated significant CAILS score reductions (mean 23.75 to 9.2, 20.9 to 14.3, both p<0.001, respectively), indicative of a systemic response. Pruritus and pain scores did not significantly change (3.33 to 2.91, p = 0.72; 2.75 to 0.67, p = 0.079). Histological analyses confirmed improvement suggestive of an abscopal effect in 33% of patients. Common adverse events included mild-to-moderate lesion irritation, swelling, dryness, pain and bleeding, without need for early IMQ discontinuation except in one patient. Conclusion Preliminary results from this pilot study indicate that topical IMQ combined with RT is generally safe and efficacious for MF, demonstrating significant clinical and histological responses, including evidence of an abscopal effect. Ongoing analyses will further investigate associated proteomic, transcriptomic, and metagenomic changes to enhance our understanding of the underlying immunologic mechanisms.