MADRID – participating in the large, prospective, observational APPLES study, Regina Folster-Holst, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
Dr. Regina Folster-Holst
With nearly 45,000 person-years of follow-up in APPLES (A Prospective Pediatric Longitudinal Evaluation Study), there were no lymphomas and just a single case of skin cancer. That’s highly reassuring, since those were the two types of malignancies singled out as being of particular concern in the boxed warnings for the topical calcineurin inhibitors tacrolimus and pimecrolimus mandated by U.S. and European regulatory agencies in 2005, noted Dr. Folster-Holst, professor of dermatology at Christian Albrechts University of Kiel (Germany).
APPLES included 7,954 children with moderate or severe AD who were a median of 6 years old at enrollment in the study, conducted at 314 sites in the United States, Canada, and seven European countries. This was a naturalistic study in which patients used the topical calcineurin inhibitor as needed, with no restrictions.
A total of six cancers were diagnosed in six individuals during 44,629 person-years of prospective follow-up: one case each of chronic myeloid leukemia, alveolar rhabdomyosarcoma, malignant paraganglioma, carcinoid tumor of the appendix, spinal cord neoplasm, and Spitzoid melanoma. None of those malignancies are classically associated with immunosuppressive therapy.
The primary outcome in APPLES was the standardized incidence ratio of observed cancers to the expected number based upon extrapolation from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, as well as national cancer registries in the other countries where the study was carried out. The expected number of cancers was 5.95, yielding a standardized incidence ratio of 1.01.
Only 27% of patients completed the study. Investigators had anticipated a substantial attrition rate and recalculated their statistics based upon a range of hypothetically increased cancer rates among the dropouts. Even if the cancer rate was 2.5-fold higher in dropouts than in those who remained in the study – a far-fetched possibility – the standardized incidence ratio would not be significantly affected, according to Dr. Folster-Holst.
The new APPLES findings were preceded by a favorable report on long-term use of topical pimecrolimus from the Pediatric Eczema Elective Registry (PEER). The study included 7,457 pimecrolimus-using children with AD followed for 26,792 person-years. The standardized incidence ratio for all cancers was not significantly increased at 1.2. The investigators concluded “it seems unlikely” that topical pimecrolimus as generally used for treatment of AD is associated with an increased risk of malignancy (JAMA Dermatol. 2015 Jun;151[6]:594-9).
The boxed warnings for the topical calcineurin inhibitors have been the source of enormous frustration for dermatologists. The warnings were ordered because of regulatory concern about an increased risk of malignancy in organ transplant recipients on systemic calcineurin inhibitors for immunosuppression, even though the topical agents – unlike the systemic versions – are used intermittently, their systemic absorption is low to nil, and no plausible mechanism by which they could cause cancer has been put forth. Many physicians believe these drugs are probably safer than topical corticosteroids, so the first question put to Dr. Folster-Holst from the audience was, When will the boxed warnings be removed?
“That’s a good question,” she replied. “Patients and parents are afraid. But I think we have now a good argument to move forward with topically applied calcineurin inhibitors.”
Dr. Folster-Holst reported having no financial conflicts of interest regarding the APPLES study, funded by LEO Pharma.