BackgroundIpilimumab, 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 FindingsPatient 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 patientś 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.ConclusionThe 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.
Ipilimumab is besides the BRAF inhibitor vemurafenib the first officially approved medical treatment for metastatic melanoma, which results in improved survival. Ipilimumab leads to a release of a CTLA4-mediated inhibition of T-cell immunoreactions. Therefore, patients may also suffer from immune-related adverse events affecting different organs, which are typically treated by high-dose corticosteroids. Ipilimumab-induced hypophysitis (iH) has been reported in up to 17% of melanoma patients in clinical trials.Here we present 5 patients with metastatic melanoma and 2 patients with prostate cancer who developed hypophysitis after ipilimumab therapy. Patients were treated by high-dose corticosteroid therapy resulting in the resolution of local inflammation but not of pituitary deficiencies. Partial or complete hypopituitarism remained in all patients. Pharmacotherapy with high-dose corticosteroids caused complications in 5 patients, necessitating hospitalization in 4. 2 of the 3 patients with progressive disease died, while 3 patients had stable disease and 1 patient showed tumor regression after discontinuation of ipilimumab.In summary, with regard to safety and simplicity of hormonal substitution therapy we have to scrutinize high-dose corticosteroid therapy, though it only improves inflammation but not neuro-endocrine function and may cause further morbidity. Regression of the tumor depends on the ipilimumab-mediated immune events, in which high-dose and long-term corticosteroid therapy for iH appears to be counter-intuitive. Herein, we discuss screening and the diagnostic as well as therapeutic management of iH in metastatic cancer patients from an endocrinologic perspective.
Checkpoint inhibitors induce a plethora of immune-related adverse events (irAEs) including autoimmune colitis, hepatitis, endocrinopathies, and rarer side effects like neuritis. Here, a case of autoimmune cardiomyopathy (grade 3 CTCAE) and myocarditis under combination therapy with nivolumab plus ipilimumab in a 72-year-old melanoma patient is reported. Treatment induced a partial response for 14 months. However, after 10 infusions the patient developed dyspnea, edema of the legs, ascites and a weight gain of 10 kg because of a decompensated heart insufficiency with a reduced ejection fraction from formerly 48%-50% to 15%. Ischemia and viral infections were ruled out. Histopathology showed hypertrophic myocarditis with interstitial lymphocytes. Prednisolone improved the patient's condition within 3 days, leading to a 25% and 30% ejection fraction after 2 and 8 weeks, respectively, and clinical symptoms subsided completely. Importantly, reinduction of anti-PD1 therapy resulted in a flare of myocarditis. Awareness for potentially life-threatening irAE of checkpoint inhibitors like autoimmune cardiomyopathy and myocarditis is crucial to rapidly initiate adequate treatment.
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