Severe cutaneous adverse reactions induced by targeted anticancer therapies and immunotherapies

Abstract

With the increasing use of targeted anticancer drugs and immunotherapies, there have been a substantial number of reports concerning life-threatening severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome, and acute generalized exanthematous pustulosis. Although the potential risks and characteristics for targeted anticancer agent- and immunotherapy-induced SCAR were not well understood, these serious adverse reactions usually result in morbidity and sequela. As a treatment guideline for this devastating condition is still unavailable, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we outline distinct types of SCARs caused by targeted anticancer therapies and immunotherapies. Also, we discuss the clinical course, latency, concomitant medication, tolerability of rechallenge or alternatives, tumor response, and mortality associated with these devastating conditions. Imatinib, vemurafenib, and rituximab were the top three offending medications that most commonly caused SJS/TEN, while EGFR inhibitors were the group of drugs that most frequently induced SJS/TEN. For drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome and acute generalized exanthematous pustulosis, imatinib was also the most common offending drug. Additionally, we delineated 10 SCAR cases related to innovative immunotherapies, including PD1 and CTLA4 inhibitors. There was a wide range of latency periods: 5.5-91 days (median). Only eight of 16 reported patients with SCAR showed clinical responses. Targeted anticancer drugs and immunotherapies can lead to lethal SCAR (14 deceased patients were identified as suffering from SJS/TEN). The mortality rate of TEN was high: up to 52.4%. The information compiled herein will serve as a solid foundation to formulate ideas for early recognition of SCAR and to discontinue offending drugs for better management.

Keywords: Stevens–Johnson syndrome; acute generalized exanthematous pustulosis; drug rash; eosinophilia; immunotherapy; targeted therapy; toxic epidermal necrolysis.

Figure 1

Fatal toxic epidermal necrolysis after cetuximab treatment for 8 weeks. Notes: A 74-year-old man who had moderately differentiated metastatic colon adenocarcinoma presented diffuse erythematous plaques with dusky red centers on trunk and extremities after treatment with cetuximab for 8 weeks. The skin rashes were confluent and formed large blisters or skin detachments involving more than 70% of the body surface area.

Figure 2

Drug rash with eosinophilia and systemic symptoms after erlotinib treatment for 4 weeks. Notes: A 60-year-old woman with EGFR-mutant metastatic lung adenocarcinoma treated with erlotinib for 4 weeks. She developed generalized infiltrative exanthema on trunk and limbs accompanied by fever, acute liver failure, coagulopathy, and leukocytosis with eosinophilia. Further lymphocyte activation testing confirmed a hypersensitivity reaction to erlotinib.