Mycosis fungoides (MF) is the most common subtype of cutaneous T cell lymphoma (MF) and presents as cutaneous patches, plaques, and tumors. Radiation therapy (RT) is a frequently pursued management option for CTCL, especially in patients with more advanced skin disease. Imiquimod stimulates a Th1 lymphocyte response with increased IL-2 and IFN-α, but also induces IFN-α, TNF-α, IL-1α, IL-6, and IL-8, thereby bridging both innate and adaptive immunity. Dosing of both radiotherapy (RT) and imiquimod are based on standard-of-care doses/frequencies for CTCL. The reason imiquimod topical is given for a week before giving RT is to prime innate immune activity for when RT is delivered. It is believed that this serves as an adjuvant for the CD8+ antitumor response generated by RT. The primary aim of this study is to assess the safety and efficacy of a combination local radiotherapy and topical imiquimod approach for the treatment of conventional (CD4+) MF.

Inclusion Criteria:

• Patients must have confirmed stage IA-IIB mycosis fungoides.
• Patients must be 18-90 years of age.
• Patients must have failed at least one standard therapy for MF.
• Patients must have active, but stable disease for >6 months.
• Patients must have 4 or more discrete MF lesions with at least 2 of them with minimum combined surface area of >50cm2.
• POCBP must have a negative pregnancy test prior to registration on study.
• Patients must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Patients who are on current systemic or topical CTCL therapy, unless stable on the treatment for >6 months.
• Patients who have received antibiotic therapy within 4 weeks of study enrollment.
• Patients who are pregnant or nursing. Pregnant people are excluded from this study because IMQ is an agent with potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the gestational parent with IMQ, breastfeeding should be discontinued if the parent is treated with IMQ.
• Patients with psychiatric illness/social situations that would limit compliance with study requirements.