A Safety Assessment of Topical Calcineurin Inhibitors in the Treatment of Atopic Dermatitis

Mark Lebwohl, MD; Tara Gower, PhD

Disclosures

October 10, 2006

Reports of Malignancies in Clinical Trials

As a class, TCIs have been studied extensively in clinical trials, and practitioners have broad clinical experience treating millions of patients. Overall, the rate of malignancy in patients who have been treated with TCIs is no more than what is expected in the general population, even when taking underreporting into account.[36] More specifically, in clinical trials of tacrolimus, there have been no reports of malignancy (lymphoma or skin cancer) or lymphoproliferative disease.[52] In the > 21,000 patients who were treated with pimecrolimus cream 1% in clinical trials, 2 malignancies have been reported (1 squamous cell carcinoma, 1 colon cancer). In contrast, 5 malignancies have been reported in the approximately 4000 patients in the control groups in these clinical trials. These malignancies included gastric cancer, melanoma, malignant histiocytosis, and leukemia in patients who received topical corticosteroids, and thyroid cancer in patients who received vehicle cream only.[37,38]

In clinical practice, it is estimated that > 11 million patients have been treated worldwide with tacrolimus ointment or pimecrolimus cream 1% since their approval in 2000 and 2001, respectively. Postmarketing surveillance has not revealed any increased risk for malignancy, including lymphoma and skin cancer, in patients treated with TCIs when compared with an analysis of data in the Surveillance, Epidemiology, and End Results (SEER) database.[37,52] The age-adjusted incidence rate of non-Hodgkin's lymphoma, with SEER cancer registries from 1973 to 2001, is 16.7 cases per 100,000 patient-years. Specifically, the total exposure in the United States with pimecrolimus cream 1% is > 733,000 person-years, with the most exposure time occurring in children.[37] It may be difficult to assess the true risk for malignancy with TCIs because it is difficult to quantify total TCI use, and there is also a potential for underreporting of cases. However, the trend indicates no link between TCI use and lymphoma.

Before the TCI label changes, an independent panel of experts (specialties included dermatology, epidemiology, and oncology) evaluated the lymphoma cases.[53] The panel concluded that there was "no clear link" between TCI use and lymphoma, partly because the reported cases of lymphoma do not match the type of lymphomas that have been seen with posttransplant lymphoproliferative disorder (PTLD). The majority of lymphoma cases associated with PTLD present in unusual locations and have a polymorphic-related, B-cell-related, and Epstein-Barr virus-related pathology.[53] In addition, about half of all PTLD-related lymphomas regress after cessation of immunosuppressive therapy.[53] Also, it is important to note that due to an overlap in clinical presentation between cutaneous T-cell lymphoma and AD, reported cases of cutaneous T-cell lymphoma in patients who have been treated with TCIs may represent a potential initial misdiagnosis.

At the time of the label changes, no cases of skin cancer had been reported in pediatric patients during postmarketing surveillance of TCIs; however, an increased risk for skin malignancy following sun exposure was noted in patients who have been treated with systemic calcineurin inhibitors (ie, cyclosporine A and tacrolimus).[54] Although this increased risk for skin malignancy is generally believed to be the result of systemic immune suppression by these agents, recent in vitro studies suggested that local effects (ie, inhibition of DNA repair and apoptosis) might also play a role.[55] This hypothesis was not supported by murine studies in which topically administered tacrolimus ointment 0.1%, pimecrolimus cream 1%, or vehicle protected against ultraviolet light-induced DNA damage.[54] In another study that evaluated the effects of topical tacrolimus on skin carcinogenesis, 117 mice were pretreated with 7,12-dimethylbenz[a]anthracene (DMBA) dissolved in acetone and/or 12-O-tetradecanoylphorbol-13-acetate (TPA), which are known tumor initiators. This study showed that subsequent treatment with topical tacrolimus ointment 0.1% increased the induction of skin tumors, particularly benign papillomas, not squamous cell carcinomas.[56] Additional long-term safety studies as well as patient registries are ongoing to further establish the safety profile of TCIs.

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