Background: Immunotherapy with checkpoint inhibition represents a significant development in the management of advanced malignancies. Toxicity associated with this therapy, or immune-related adverse events (irAEs), is most frequently seen in the form of colitis, dermatitis, pneumonitis, or hepatitis. Prompt initiation of high-dose corticosteroids in severe cases is essential. Refractory toxicity can be seen and requires a multimodality approach.
Case Report : A 68 year old male with a history of stage IVB squamous cell carcinoma (SCC) and an illdefined left renal mass (4.8 × 4.1 cm2, presumed urothelial carcinoma) was successfully maintained on nivolumab monotherapy for nearly two years. However, after 45 cycles he presented to the emergency department with acute hypoxic respiratory failure. He was admitted and found to have multifocal pulmonary consolidations refractory to empiric antibiotics. Ultimately his symptoms were attributed to nivolumab-induced pneumonitis. He improved on corticosteroids and was discharged with a prednisone taper. One month later he returned with severe lower extremity weakness, an elevated creatinine kinase, grade IV hepatitis, and hematuria. Notwithstanding immediate escalation to intravenous methylprednisolone (2 mg/kg) and a trial of IVIG, his myositis and liver dysfunction worsened. Mycophenolate mofetil was added (1000 mg BID) and successfully reversed his creatinine kinase (from 3633 U/L); however, his hepatitis continued to progress (total bilirubin to 16.4 mg/dL). After further discussion with gastroenterology, tacrolimus was also started (2 mg BID) and caused gradual improvement in his transaminases. Once stabilized, he underwent a left nephrectomy for persistent hematuria; pathology results revealed an unusual focus of metastatic SCC. Unfortunately, he developed post-operative bleeding complications and CMV viremia. He elected to pursue comfort measures and passed 2 weeks later.
Conclusion: Checkpoint inhibitor toxicities can demonstrate delayed presentations despite numerous cycles of successful therapy. In cases where aggressive corticosteroid therapy is unsuccessful, additional immunomodulatory agents are required to curb progression of organ-specific damage. Close surveillance for opportunistic infections must be maintained. Additional studies are needed to assess whether earlier discontinuation of checkpoint inhibition is feasible in patients with sustained responses to minimize late irAEs.
