Risk factors and immunomodulators use in steroid-refractory checkpoint inhibitor pneumonitis

Background Checkpoint inhibitor pneumonitis (CIP) that does not respond to corticosteroids is termed steroid-refractory CIP. We aimed to find risk factors of steroid-refractory CIP and evaluate the management strategies of immunomodulators (IMs). Methods Patients with CIP were identified between August 2019 and August 2022 retrospectively. Clinical characteristics, peripheral blood biomarkers, and radiologic images were collected. Results Among 1209 patients with solid tumor receiving programmed death (ligand)-1 antibody, 28 patients developed steroid-refractory CIP and 38 patients developed steroid-response CIP. Patients with steroid-refractory CIP had a higher proportion of previous interstitial lung disease (p=0.015) and grade 3–4 (p<0.001) at diagnosis. Otherwise, absolute neutrophil count (ANC), procalcitonin were higher and albumin was lower in steroid-refractory patients (ANC, p=0.009; procalcitonin, p=0.024; albumin, p=0.026). After multivariate analysis, grade 3–4 and higher ANC at diagnosis were confirmed to be independent risk factors for steroid-refractory CIP (grade, p=0.001; ANC, p=0.046). For grade 2 steroid-refractory CIP, additional IMs did not affect the prognosis (p=1.000). However, additional IMs reduced the risk of deterioration significantly in grade 3–4 steroid-refractory CIP (p=0.036). Conclusions Grade 3–4 and higher peripheral blood ANC at diagnosis are associated with higher risk of steroid-refractory CIP. The use of additional IMs improves the outcome of grade 3–4 steroid-refractory CIP. These results can offer new insights to the decision-making of CIP management.

[1]  M. Strek,et al.  Lung function trajectory in progressive fibrosing interstitial lung disease , 2021, European Respiratory Journal.

[2]  M. Suarez‐Almazor,et al.  Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update , 2021, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  J. Marshall,et al.  Upregulated PD-L1 delays human neutrophil apoptosis and promotes lung injury in an experimental mouse model of sepsis. , 2021, Blood.

[4]  R. Sullivan,et al.  Immune-related toxicities of checkpoint inhibitors: mechanisms and mitigation strategies , 2021, Nature Reviews Drug Discovery.

[5]  E. Gabbay,et al.  Patterns of immunotherapy-induced pneumonitis in patients with non-small-cell lung cancer: a case series , 2021, Journal of Medical Case Reports.

[6]  P. Ascierto,et al.  Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events , 2021, Journal for ImmunoTherapy of Cancer.

[7]  M. Kris,et al.  Beyond steroids: immunosuppressants in steroid-refractory/resistant immune related adverse events. , 2021, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[8]  F. Hodi,et al.  Effect of corticosteroid dosing on outcomes in high‐grade immune checkpoint inhibitor hepatitis , 2021, Hepatology.

[9]  T. Schwartz,et al.  Immune checkpoint inhibitor-related pneumonitis in lung cancer: real-world incidence, risk factors, and management practices across six health care centers in North Carolina. , 2021, Chest.

[10]  M. Voss,et al.  Success and failure of additional immune modulators in steroid-refractory/resistant pneumonitis related to immune checkpoint blockade , 2021, Journal for ImmunoTherapy of Cancer.

[11]  Y. Nakanishi,et al.  Continuous monitoring of neutrophils to lymphocytes ratio for estimating the onset, severity, and subsequent prognosis of immune related adverse events , 2021, Scientific reports.

[12]  C. Lin,et al.  Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes , 2021, Journal for ImmunoTherapy of Cancer.

[13]  S. Noma,et al.  Clinical and radiological features of immune checkpoint inhibitor-related pneumonitis in lung cancer and non-lung cancers. , 2020, The British journal of radiology.

[14]  C. Lin,et al.  Chronic immune checkpoint inhibitor pneumonitis , 2020, Journal for immunotherapy of cancer.

[15]  J. Farkas Immune-related adverse events of checkpoint inhibitors , 2020, Nature Reviews Disease Primers.

[16]  J. Larkin,et al.  EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors , 2020, Annals of the Rheumatic Diseases.

[17]  Siddharth Singh,et al.  Comparative Risk of Serious Infections With Biologic and/or Immunosuppressive Therapy in Patients With Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis. , 2020, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[18]  N. Ramaiya,et al.  Immune Checkpoint Inhibitor Therapy-related Pneumonitis: Patterns and Management. , 2019, Radiographics : a review publication of the Radiological Society of North America, Inc.

[19]  W. Travis,et al.  Knowledge Gaps and Research Priorities in Immune Checkpoint Inhibitor–related Pneumonitis. An Official American Thoracic Society Research Statement , 2019, American journal of respiratory and critical care medicine.

[20]  Sheila K. Wang,et al.  Steroid Side Effects. , 2019, JAMA.

[21]  C. Lin,et al.  Pneumonitis in Non–Small Cell Lung Cancer Patients Receiving Immune Checkpoint Immunotherapy: Incidence and Risk Factors , 2018, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[22]  K. Jahn,et al.  Treatment of mycophenolate-resistant immune-related organizing pneumonia with infliximab , 2018, Journal of Immunotherapy for Cancer.

[23]  T. Mio,et al.  Concurrence of nivolumab‐induced interstitial lung disease and cancer invasion , 2017, Respirology case reports.

[24]  C. Rudin,et al.  Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  F. Nimmerjahn,et al.  Intravenous immunoglobulin therapy: how does IgG modulate the immune system? , 2013, Nature Reviews Immunology.

[26]  N. Müller,et al.  Acute interstitial pneumonia: comparison of high-resolution computed tomography findings between survivors and nonsurvivors. , 2002, American journal of respiratory and critical care medicine.

[27]  G. Coukos,et al.  New therapeutic perspectives to manage refractory immune checkpoint-related toxicities. , 2019, The Lancet. Oncology.