A Multidisciplinary Approach to Improve the Management of Immune-Checkpoint Inhibitor-Related Pneumonitis

Abstract

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.

Keywords: cancer; immune-checkpoint inhibitors; immune-mediated pneumonitis; immunotherapy.

Graphical abstract

Figure 1

Time of im-PN resolution. Treatment with steroids leading to resolution of G1-2im-PN according to CTCAE v. 5.0 in 95% of subjects, with a median time to resolution of 14 weeks [range: 0.4–51].

Figure 2

Cytology evaluation of bronchoalveolar lavage and transmission electron microscopy in an OP-like im-PN case. Chest CT scan depicted in MM patient an OP-like pattern of im-PN at diagnosis (panel A) and after recovery (panel B). Bronchoalveolar lavage sample analysis (panels C and D) showed an inflammatory lymphocytic infiltrate, predominantly consisting of foam cell-like macrophages characterized by micro- and macro-vacuolization (panel C, 40x, papanicolau staining; panel D, detail of panel C). Transmission electron microscopy evaluation of bronchoalveolar lavage samples revealed multilamellar bodies (panel E), lysosomes, and lipid vacuoles in the alveolar macrophages (panel F, black arrow), a scenario suggestive of a drug-mediated toxicity.