Pneumonitis after immune checkpoint inhibitor therapies in patients with acute myeloid leukemia: A retrospective cohort study

Abstract

Background Immune checkpoint inhibitors (ICI), combined with hypomethylating agents, can be used to treat acute myeloid leukemia (AML), but this strategy results in a high rate of pneumonitis. The authors sought to determine risk factors for pneumonitis development and whether pneumonitis increased mortality. Methods The authors conducted a retrospective review of 258 AML patients who received ICI‐containing regimens from 2016 to 2018. A multidisciplinary adjudication committee diagnosed pneumonia and pneumonitis by reviewing symptoms, imaging, microbiology, and response to therapies. To measure risk factors for pneumonitis and mortality, multivariate Cox proportional hazards models were constructed. Pneumonia, pneumonitis, and disease progression were modeled as a time‐dependent variable and incorporated a standard risk set modifying variables into the models. Results Thirty patients developed pneumonitis (12%). Of these, 17 had partial or complete resolution, whereas 13 patients died from pneumonitis. Increasing age (hazard ratio [HR], 1.04 per year; 95% confidence interval [CI], 1.00‐1.08), and baseline shortness of breath increased pneumonitis risk (HR, 2.51; 95% CI, 1.13‐5.55). Female sex (HR, 0.33; 95% CI, 0.15‐0.70) and increasing platelet count (HR, 0.52 per log‐unit increase; 95% CI, 0.30‐0.92) decreased pneumonitis risk. In adjusted models, ICI‐related pneumonitis significantly increased mortality (HR, 2.84; 95% CI, 1.84‐4.37). Conclusions ICI‐related pneumonitis occurs at a high rate in AML patients and increases mortality. Lay Summary Immune checkpoint inhibitors (ICIs) remove inhibitory signals that reduce T‐cell function and allow T‐cells to better attack cancer cells. In acute myeloid leukemia (AML), the effectiveness of ICIs is limited in part by inflammation of the lung, called pneumonitis. This study reviewed 258 patients with AML who received ICIs and identified 30 patients who developed pneumonitis, nearly half of whom died. Older age and baseline shortness of breath increased pneumonitis risk, whereas female sex and higher baseline platelet counts decreased pneumonitis risk. Pneumonitis increased mortality by nearly 3‐fold. This work highlights the significant harm imposed by pneumonitis after ICI therapies.

Common methodological pitfalls in ICI pneumonitis risk prediction studies

“…Missing values were reported in 22/50 studies, the maximum proportion of missing values in a single-variable ranges between 0.2% and 64.7% across the studies (median:17.3%, IQR: 7.5%-36.1%). 4/22 of the studies included the missing values as a separate level in regression analysis ( 11 , 35 , 41 , 46 ), 5/22 were unclear about the imputation method used ( 19 , 21 , 39 , 61 , 64 ), the rest simply excluded subjects with missing values. None of the studies investigated whether the missing values were independent from values in other variables.…”

“…Survival analysis was the second most popular method for univariate analysis, and was performed in 8/47 studies that conducted univariate analysis: 5/8 studies used survival analysis alone to identify risk factors (2 applied the Fine-Gray test, 3 applied Cox proportional hazard model) ( 40 , 46 , 53 , 61 , 63 ). One study conducted a contingency test and used a Cox proportional hazard model on the same factor ( 49 ), the other two used contingency and/or two-sample tests to select variables that should be further assessed in univariate survival modelling ( 39 , 58 ).…”

“…Multivariable analysis was performed in 31/51 studies, most of them (23/31) used only logistic regression, another 6/31 used only survival modelling (3 with the Fine-Gray test, 3 with the Cox proportional hazard model) ( 39 , 40 , 46 , 53 , 61 , 63 ). One study implied the existence of multivariable analysis for ICI pneumonitis but did not report corresponding results ( 50 ), the other applied both logistic regression and Cox proportional hazard model ( 58 ).…”

Characterization of immunomodulatory factors and cells in bronchoalveolar lavage fluid for immune checkpoint inhibitor-related pneumonitis

“…Delaunay et al (2017) reported BAL findings in 35 samples from a cohort of 64 ICI-pneumonitis patients, and 68.5% of these patients have BAL lymphocytes > 15%. However, in a study by (Sheshadri et al 2022), lymphocytosis was not a distinctive feature of pneumonitis in patients with leukemia who underwent BAL. In addition, eosinophils were also found in some cases (Hara et al 2021).…”

Pulmonary Immune-Related Adverse Events of PD-1 Versus PD-L1 Checkpoint Inhibitors: A Retrospective Review of Pharmacovigilance

“…An explanation for the differences in risk of ICI-related pulmonary irAEs is the possible variations in immune responses between both sexes. [ 20 ] The female sex is hypothesized to mount a stronger innate and adaptive immunity, resulting in less susceptibility to ICI-related irAEs than the male sex. [ 31 – 33 ] A retrospective study on ICI-related pneumonitis in patients with acute myeloid leukemia found it to be most remarkable in the male than in the female sex.…”