The Price of Tumor Control: An Analysis of Rare Side Effects of Anti-CTLA-4 Therapy in Metastatic Melanoma from the Ipilimumab Network

Abstract

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.

ENDOCRINE SIDE-EFFECTS OF ANTI-CANCER DRUGS: mAbs and pituitary dysfunction: clinical evidence and pathogenic hypotheses

“…IRAEs induced by anti-CTLA4-mAbs were mild to moderate in most patients, and the recovery was obtained by medical treatments as indicated in protocol guidelines (32). However, more severe grade of IRAEs, particularly severe or life-threatening diarrhea/colitis/diverticulitis, hepatitis, and hypophysitis and even drug-related deaths (2.2%) were reported (33,34). In the majority of cases, the onset of IRAEs seems to depend on the organ damaged by the drug (33,35).…”

Dermatologic adverse events associated with chemotherapy and targeted anticancer therapy

“…Osutka ma charakter odropodobny, zajęta jest twarz, górna część tułowia i kończyny, istnieje możliwość przejścia w erytrodermię. W leczeniu stosuje się ogól-nie duże dawki glikokortykosteroidów [60,61]. Do ciężkich, zagrażających życiu, rzadkich powikłań należy SJS i TEN.…”

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“…Rare dermatological toxicities include Stevens Johnson syndrome, toxic epidermal necrolysis [7,10,21] drug rash with eosinophilia and systemic symptoms (DRESS) [21] and sweet syndrome [22]. These severe adverse effects are more frequent in anti-CTLA-4 and anti-PD-1 immunotherapy combination with an incidence of 4.8% [2].…”

“…Also, in patients with ICPIinduced encephalitis, N-methyl-D-aspartate receptor (NMDAR) immunoglobulin G antibodies were detected in the cerebrospinal fluid which are also expressed on melanocytes [42,44]. Other neurological irAEs include Myasthenia Gravis-like syndrome [43], posterior reversible leukoencephalopathy [46], aseptic meningitis [21], radiculoneuropathy [47], transverse myelitis [43] and Bell's palsy [40].…”