Corticosteroid-resistant immune-related adverse events: a systematic review

Abstract

Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient's immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend-as first line treatment-(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days.

Keywords: Immune Checkpoint Inhibitors; Review.

Figure 1

Overview of different activities of immunosuppressants used in the treatment of immune-related organ toxicities. Standard treatment of immune-mediated liver toxicities includes MMF that targets purine synthesis and thereby limits T cell-mediated anti-liver toxicity (upper left quadrant). Secondary immune suppression in patients with colitis consists of biologics targeting TNF-α (eg, infliximab) or integrins (vedolizumab, upper right quadrant). Secondary immune suppression for lung toxicities of ICI includes MMF and IVIG (lower left quadrant). Treatment of steroid-refractory myocarditis can include MMF, abatacept (fusion protein with CTLA-4 inhibiting CD80/86 interactions), ruxolitinib (JAK 1/2 inhibitor) or ATG (lower right).APC, antigen presenting cell; HLA, human leukocyte antigen; IV, intravenous; MHC, major histocompatibility complex; MMF, mycophenolate mofetil; TCR, T cell receptor.