Topical Calcineurin Inhibitors and Lymphoma Risk: Evidence Update with Implications for Daily Practice

Abstract

Topical calcineurin inhibitors (TCIs), commercially available since 2000–2001, are the first and only topical medications approved for chronic treatment of atopic dermatitis (AD) in pediatric patients and remain a welcomed alternative to topical corticosteroids. In January 2006, the US Food and Drug Administration (FDA) issued a boxed warning requirement based on a theoretical risk of malignancy (including lymphoma) with TCI use. However, in the years since, analyses of epidemiologic and clinical data have failed to demonstrate a causal relationship between TCI use and malignancy or lymphoma risk, especially for pimecrolimus cream. In fact, the observed number of malignancies and lymphomas observed both in post-marketing surveillance and reported to the FDA using its adverse events reporting system is much lower among TCI-exposed patients than the expected number for the general population. Furthermore, among children enrolled in post-marketing pediatric registry studies for both tacrolimus and pimecrolimus followed for up to 5.5 years [10,724 patient-years (PY)] or 6.5 years (16,219 PY), respectively, the observed number of malignancies and lymphomas is very low and similar to the number expected for a sample of similar size in the general population. In addition to reporting these comparative malignancy and lymphoma data, this article provides a historical overview of the boxed warning requirement and critically evaluates the preclinical, clinical, and epidemiological evidence that has thus far failed to substantiate a relationship between TCI use and malignancy. The authors also provide practical clinical advice for optimizing AD management and patient care in the context of the boxed warning.

Topical Calcineurin Inhibitors and Malignancy Risk

“…In the cohort study by Margolis et al the RR of lymphoma in patients with severe AD was 1.95 (95% CI, 1.15 -3.12) (45) while in the two case control studies the adjusted OR varied from 2.4 (95% CI, 1.5 -3.8) to 3.72 (95% CI, 1.40 -9.87) (21,22). However, considering the potential misclassification bias and possibility of independent association between atopic dermatitis and risk of developing lymphoma, this result should be interpreted with caution (47). Because of the overlapping clinical presentations, early forms of cutaneous T-cell lymphoma (CTCL) might have been initially misdiagnosed for severe AD.…”

Topical Treatment Utilization for Patients with Atopic Dermatitis in the United States and Budget Impact Analysis of Crisaborole Ointment, 2%

“…TCS V-VII only (representing low potency TCS) 4. TCS I-VII (any multiple excluding above) 5. TCI only 6.…”

Addressing treatment challenges in atopic dermatitis with novel topical therapies

“…There is also some concern regarding the potential prevalence of viral infection with TCIs because of several case reports attributing eczema herpeticum to TCI use; thus, TCI use on infected lesions is not recommended (2,29). Although TCIs are generally considered safe for the management of AD (29), the addition of a boxed warning for them by the US Food and Drug Administration (FDA) in 2006 regarding a potential risk for malignancy has resulted in hesitancy to prescribe them (28,37). Despite recent reports that question the validity of this claim, the FDA has retained the warning, citing that there may still be a possible association between TCIs and an increased risk for lymphoma (27,37,38).…”

“…Although TCIs are generally considered safe for the management of AD (29), the addition of a boxed warning for them by the US Food and Drug Administration (FDA) in 2006 regarding a potential risk for malignancy has resulted in hesitancy to prescribe them (28,37). Despite recent reports that question the validity of this claim, the FDA has retained the warning, citing that there may still be a possible association between TCIs and an increased risk for lymphoma (27,37,38). The lower range of efficacy and the boxed warning make long-term treatment with TCIs somewhat challenging.…”