RESUMO
Purpose: Treatment with immune-checkpoint inhibitors (ICIs) can be associated with a wide spectrum of immune-related adverse events (irAEs). Among irAEs, immune-mediated pneumonitis (im-PN) is a rare but potentially life-threatening side effect. TPrompt multidisciplinary diagnosis and effective management of im-PN may be essential to avoid severe complications and allowing resumation of therapy. Patients and Methods: We collected a case series of skin (melanoma, cutaneous squamous cell carcinoma-CSCC), lung, and mesothelioma cancer patients (pts), treated with ICI at the Center for Immuno-Oncology University Hospital of Siena, Italy, and diagnosed with im-PN. Clinical and radiologic data were thoroughly collected, as well as bronchoalveolar lavage (BAL) samples; im-PN was graded using CTCAE v. 5.0. Radiological patterns were reported according to the Fleischner Society classification. Results: From January 2014 to February 2023, 1004 patients with melanoma (522), CSCC (42), lung (342) or mesothelioma (98) were treated with ICI (619 monotherapy; 385 combination). Among treated patients, 24 (2%) developed an im-PN and 58% were symptomatic. Im-PN were classified as grades G1 (10) and G2 (14). Prompt steroid treatment led to complete resolution of im-PN in 21 patients, with a median time to resolution of 14 weeks (range: 0.4-51). Twelve patients resumed ICI therapy once fully-recovered and 2 experienced a recurrence that completely resolved with steroids after resumption of treatment. Three radiologic patterns were identified: organizational pneumonia-like (67%), pulmonary eosinophilia (29%), and hypersensitivity pneumonitis (4%). Furthermore, BAL analysis performed in 8 (33%) patients showed an inflammatory lymphocytic infiltrate, predominantly consisting of foam cell-like macrophage infiltrates in 6 cases. Notably, transmission electron microscopy evaluation performed in 2 patients revealed a scenario suggestive of a drug-mediated toxicity. Conclusion: Im-PN is a rare but challenging side effect of ICI therapy, with variable time of onset and with heterogeneous clinical and radiological presentations. A multidisciplinary assessment is mandatory to optimize the clinical management of im-PN.
RESUMO
The anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) monoclonal antibody ipilimumab was the first in-class immune-checkpoint inhibitor (ICI) approved for the treatment of melanoma patients. Initially approved for metastatic cutaneous melanoma, treatment with ipilimumab subsequently demonstrated to significantly improve recurrence free survival (RFS) in fully resected, high-risk, stage III melanoma patients. Therapeutic use of ipilimumab has also allowed the initial identification and characterization of unconventional clinical and radiological patterns of response (ie, tumor flare, pseudo-progression) that may occur during ICI therapy, unlike chemotherapy or targeted therapy. As a result, the standard Response Evaluation Criteria In Solid Tumors (RECIST) and the World Health Organization (WHO) criteria conventionally utilized to assess responses to chemo/targeted therapy have been initially replaced by the immune-related (ir) Response Criteria (irRC) and then by the irRECIST, that encompass all patterns of response typical of ICI therapy, being key for the optimal comprehensive management of treated patients. Here, we report a paradigmatic clinical case of a long-term survival in a stage III melanoma patient, experiencing tumor flares during adjuvant treatment with ipilimumab, and an untreated disease relapse several years after ending therapy.