A New Topical Treatment for Cutaneous T-Cell Lymphoma

The investigational topical drug resiquimod was safe and effective in clearing treated and untreated skin lesions in patients with early-stage cutaneous T-cell lymphoma (CTCL), according to results from a phase I trial published in Blood.

Currently, the only curative therapy for CTCLs, a group of non-Hodgkin lymphomas derived from skin-homing T cells, is stem cell transplantation. While topical steroids, light therapy, and other skin-directed therapies suppress the disease, skin lesions commonly recur following the discontinuation of therapy. And, though 80 percent of patients with early-stage CTCL have a normal life expectancy, 20 percent will progress to a more aggressive disease, which can include the development of skin tumors and systemic metastases, the authors, led by Alain H. Rook, MD, from the Department of Dermatology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, explained.

“A curative therapy is needed, both to eradicate disease when it is still manageable in patients who will progress and to spare patients with stable disease from lifelong skin-directed therapies that can weaken the immune system and put patients at increased risk for skin cancer,” Dr. Rook and colleagues wrote. “Given resiquimod’s ability to stimulate dendritic cells in both healthy and inflamed skin, we chose this medication to test in the treatment of CTCL.”

Resiquimod gel is an imidazoquinoline with potent stimulating activity of Toll-like receptors TLR7 and TLR8, modifying the immune response. In the phase I trial, researchers evaluated two concentrations of topical resiquimod gel (0.06% and 0.03%) applied to a limited number of skin lesions in a small group of patients with stage IA and IIA CTCL.

All patients had a pretreatment, four-week washout period to discontinue prior CTCL therapies, and were then instructed to apply up to 500 mg of resiquimod gel to four target lesions in the 0.06 percent group or up to five target lesions in the 0.03 percent group.

Dosing started at three times per week, and patients were evaluated every two weeks until a maximum of 24 weeks. Dosing frequency (up to seven times weekly) was adjusted in a stepwise manner after each physician’s evaluation of each patient’s tolerability.

Resiquimod was applied for eight weeks followed by a four-week discontinuation period to allow the treatment-induced inflammation to subside so accurate skin scores could be established. Patients were allowed to receive another eight-week course of treatment and four-week discontinuation, with a final follow-up at 24 weeks.

Twelve patients (10 with stage IB CTCL, one had stage IA, and one had stage IIA) completed therapy. Five patients had folliculotropic disease. Patients received a mean of six prior therapies; some received as many as 11 prior therapies.

The researchers found that resiquimod induced regression of both treated and untreated lesions: eleven patients (92%) experienced significant improvement by the end of the study period, defined as a >50 percent improvement in body surface area (BSA) involvement by tumor.

Seventy-five percent of patients (n=9) had a significant response to treatment, five patients experienced a partial response (defined as >50% improvement in BSA involvement), and four patients experienced a complete clinical response. The remaining three patients saw improvement with treatment, but did not meet the predetermined criteria for partial response.

Response rates were high in both dose concentrations, though the two cases of complete response occurred in the 0.06 percent treatment cohort. Response to treatment also occurred more quickly in the 0.06 percent treatment group.

“Both doses were equally well tolerated,” the authors noted, “with minor skin reactions representing the most common adverse effects.” No serious adverse events were recorded. Of the eight patients in the 0.06 percent concentration cohort, five developed superficial skin erosions at some sites of treatment, but these healed completely within one week of temporary treatment discontinuation and did not recur.

Among five patients with the difficult-to-control folliculotropic variant of CTCL, four had significant improvements in lesion severity, and one experienced a complete remission.

T-cell receptor (TCR) sequencing and flow cytometry demonstrated reduced malignant clonal T-cells in 90 percent of resiquimod-treated patients, and 30 percent of patients experienced a complete eradication of malignant T-cells. High response rates were associated with recruitment and expansion of benign T-cell clones in treated skin, increased skin T-cell effector functions, and a trend toward increased NK cell functions. In addition, 50 percent of patients had increased activation of circulating dendritic cells, consistent with a systemic response to therapy.

“Resiquimod is the first topical therapy to our knowledge that can induce clearance of untreated lesions and complete remission in some patients,” Dr. Rook and colleagues concluded. “In addition, combination therapy with resiquimod and low-dose lesional radiation to release tumor antigens is a plausible treatment approach.”


Reference

Rook AH, Gelfand JC, Wysocka M, et al. Topical resiquimod can induce disease regression, eradicate malignant T cells and enhance T cell effector functions in cutaneous T cell lymphoma. Blood. 2015 July 30. [Epub ahead of print]

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