Treatment of mycophenolate-resistant immune-related organizing pneumonia with infliximab

Abstract

Background: The development of pulmonary immune-related adverse events (irAEs) in patients undergoing PD-(L)1 targeted checkpoint inhibitors are rare, but may be life-threatening. While many published articles and guidelines are focusing on the presentation and upfront treatment of pulmonary irAEs, the strategy in patients with late-onset pneumonia that are resistant to commonly used immunosuppressive drugs remains unclear.

Case presentation: Here, we report the successful treatment of a mycophenolate-resistant organizing pneumonia (OP) with infliximab in a patient with metastatic melanoma after PD-1 blockade. The patient received two years of PD-1 targeted immunotherapy when he developed multiple nodular lung lesions mimicking a metastatic progression. However, wedge resection of these lesions showed defined areas of OP, which responded well to corticosteroids. Upon tapering, new foci of OP developed which were resistant to high-dose steroids and mycophenolate treatment. The TNFα antagonist infliximab led to a rapid and durable regression of the inflammatory lesions.

Conclusion: This case describes a not well-studied situation, in which a mycophenolate-resistant PD-1 blocker-associated pneumonitis was successfully treated with a TNFα neutralizing antibody. The outcome of this case suggests that infliximab might be the preferable option compared to classical immunosuppressants in the case of steroid-resistant/-dependent late onset pulmonary irAEs.

Keywords: Cancer immunotherapy; Immune checkpoint inhibitor; Immune-related adverse event; Lung; Pneumonitis.

Fig. 1

Initial treatment of metastatic melanoma. a ¹⁸FDG-PET-CT scan of the patient when the metastatic disease was diagnosed. b ¹⁸FDG-positive lung lesion at the initial diagnosis of metastatic BRAF mutated melanoma. c Initial treatment response to BRAF and MEK inhibitors and to pembrolizumab over time

Fig. 2

Histology of metastasis and organizing pneumonia. a, b Wedge resection of the lung after immunotherapy. The melanoma metastasis shows excellent response to treatment with extensive regressive necrosis. (HE, original magnification 25× and 200×, respectively). Here only melanin pigment and necrosis with lack of vital tumor cells are present. c, d Distant to the necrotic metastasis circumscribed areas of immunotherapy-induced organizing pneumonia with intraalveolar fibromyxoid proliferations and mild lymphoplasmacytic inflammation (HE original magnification 12,5× and 200×, respectively). (e) Immunhistochemical analysis of CD3⁺ cells in inflammatory lesions (200× magnification). f, g Staining of CD4⁺ (f) and CD8⁺ (g) cells (200× magnification). h Staining for FOXP3⁺ regulatory T cells in inflammatory lesions (200× magnification). i Immunostaining for PD-L1 in inflammatory lesions (100× magnification, SP-263 clone)

Fig. 3

Response of pulmonary inflammatory lesions to immune suppressive therapy. a CT-scan at the time point when the inflammatory lesions were first detected after 2 years of pembrolizumab therapy. b Initial response to corticosteroid therapy (1 mg/kg prednisone). Pulmonary inflammatory lesions were clearly regressing after initial therapy. c CT-scan acquired during immune suppression with mycophenolate and after tapering of prednisone (before start infliximab). d CT-scan after 6 months of infliximab therapy. No inflammatory lesions can be observed anymore. e ¹⁸FDG-PET-CT scan after the infliximab therapy was stopped. A durable remission in terms of the melanoma and the pneumopathy was found