The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network.

BACKGROUND: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. METHODS AND FINDINGS: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patients delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. CONCLUSION: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.

Sarcoidosis induced by interferon-α in melanoma patients: incidence, clinical manifestations, and management strategies.

Treatment with interferon-α has been recommended for patients with melanoma in case of micrometastases, or high risk melanoma, for example, ulcerated melanoma. Furthermore, regular dermatologic examination and regular imaging to detect recurrence or progression of disease is part of the management of melanoma patients. Sarcoidosis has been described as an adverse effect of treatment with interferon-α. Especially in hepatitis C patients, there is a series of case reports on sarcoidosis induced by interferon treatment whereas in melanoma this has rarely been reported. In a retrospective study, all melanoma patients treated with interferon-α at our hospital between 2007 and 2009 were screened for occurrence of sarcoidosis. Three of 16 melanoma patients treated with interferon-α (19%) presented with sarcoidosis. All 3 patients showed lesions with higher uptake in the positron emission tomography-computed tomography scan leading to the differential diagnosis of melanoma metastases or inflammation. Skin lesions were present in 1 patient. Diagnosis was confirmed by histologic assessment of lesions showing epithelioid granuloma-negative on Ziehl Neelson. Additional work-up included blood and urinalysis, electrocardiography, and ophthalmologic examination. Cessation of interferon-α led to regression of granulomas. Sarcoidosis induced by interferon-α in melanoma patients could be more common than previously thought. This is an important complication to be aware of as it can be mistaken for metastatic spread of melanoma and thus lead to incorrect therapy.