Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes

Abstract

BackgroundImmune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.MethodsPatients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.ResultsOf 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3–12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.ConclusionsSteroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients’ treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).

Radiation Versus Immune Checkpoint Inhibitor Associated Pneumonitis: Distinct Radiologic Morphologies

“…Among the imaging features, bilateral and multifocal involvement were significantly associated with severe pneumonitis in both the overall cohort and among patients who received RT + ICI. Similarly, previous studies have identified bilateral involvement as a risk factor for both fatal RT-pneumonitis and steroid refractory ICI-pneumonitis [30,38]. These clinical and imaging risk factors may assist in the identification of patients with NSCLC with pneumonitis who may be at high risk of clinical deterioration and may require treatment intensification for pneumonitis.…”

“…10 High-grade, steroid-refractory ICI-pneumonitis can develop in as many as 18% of patients, and may require intravenous immunoglobulin or other immunosuppressive agents such as mycophenolate mofetil or infliximab. 10,30 In addition, patients with ICI-pneumonitis are at a higher risk of recrudescence when re-challenged with ICI, while ICI rechallenge might be less problematic in patients whose pneumonitis is mainly due to RT. 31 Therefore, identifying the predominant etiology responsible for pneumonitis development after RT+ICI may help to triage patients toward the best treatment pathway.…”

“…Similarly, previous studies have identified bilateral involvement as a risk factor for both fatal RT-pneumonitis and steroid refractory ICI-pneumonitis. 30,40 These clinical and imaging risk factors may assist in the identification of NSCLC patients with pneumonitis who may be at high risk of clinical deterioration and may require treatment intensification for pneumonitis.…”

Immunotherapy-Related Cystitis: Case Report and Review of the Literature

“… 7 Several immunosuppressive agents, such as intravenous immunoglobulin mycophenolate mofetil, calcineurin inhibitors, cyclophosphamide, and methotrexate, and biological immunosuppressive agents, such as infliximab, vedolizumab, and rituximab, have been used in the management of severe or steroid-refractory irAEs. 8 Other strategies, including patient education, coordinating irAE management, prompt reporting of irAEs, and translational studies to better understand irAEs would improve the management of irAEs. 9 For continuation of ICI administration, irAEs need to be stable at grade 1 or lower on prednisone at 10mg/day.…”

Real-world insights on preferred treatments for steroid-refractory immune checkpoint inhibitor-induced pneumonitis

“…The tumor necrosis factor (TNF)-α inhibitor infliximab is often the preferred first option as it has been used successfully in other irAEs such as colitis, but there are little published data on its efficacy in treating steroid-refractory ICI-induced pneumonitis. 8 Balaji et al 9 and Beattie et al 10 present the largest retrospective chart reviews to date (n=12 and 26 patients, respectively) on the clinical management and course of patients at their respective institutions with steroidrefractory ICI-induced pneumonitis. Given the low incidence of pneumonitis and the even lower incidence of steroid-refractory pneumonitis, these retrospective reviews provide an important clinical insight into the efficacy of recommended therapies (specifically infliximab) and long-term clinical outcomes of patients with steroid-refractory ICI-induced pneumonitis.…”