Lung Function Trajectory in Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplant

Abstract

Rationale: The natural history of lung function in patients with bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplant is poorly characterized. Understanding the trajectory of lung function is necessary for prompt clinical recognition and treatment and also for the rational design of prospective studies.

Objectives: To describe the longitudinal trajectory of lung function parameters, including FEV₁, in patients with BOS after hematopoietic cell transplant.

Methods: Subjects with BOS defined by National Institutes of Health consensus guidelines criteria from a recent multicenter prospective trial of combination treatment with fluticasone, azithromycin and montelukast and a retrospective cohort from Fred Hutchinson Cancer Research Center were included. Longitudinal change in FEV₁ for each patient was calculated on the basis of available pulmonary function tests in three periods: pre-BOS, from BOS diagnosis to 6 months, and 6-18 months after diagnosis. The effect of treatment on FEV₁ trajectory was analyzed by univariate and multivariate linear regression. The Kaplan-Meier method was used to estimate survival.

Measurements and main results: The FEV₁ percent predicted value at diagnosis was 46% (interquartile range, 35-57%) for trial participants and 53% (interquartile range, 41-64%) for the retrospective cohort. There was a concomitant mild reduction in FVC, as well as a marked reduction in forced expiratory flow, midexpiratory phase, at diagnosis. While there was individual heterogeneity, the overall FEV₁ trajectory was characterized by a marked decline within 6 months prior to BOS diagnosis, followed by stability of FEV₁ early after diagnosis and a slow rate of decline beyond 6 months. The effect of the trial medications on FEV₁ trajectory after BOS diagnosis was a mean rate of change of 0.92% predicted per month (95% confidence interval, -0.53 to 2.37) compared with the retrospective cohort, but this was not statistically significant. Two-year overall survival rates were 76% and 72% for the study participants and the retrospective cohort patients, respectively. Earlier time to diagnosis after hematopoietic cell transplant and severity of FVC at diagnosis were significantly associated with reduced survival.

Conclusions: The FEV₁ trajectory in patients with BOS after hematopoietic cell transplant in a contemporary era of management follows a predominant pattern of rapid FEV₁ decline in the 6 months prior to diagnosis, followed by FEV₁ stabilization after diagnosis.

Keywords: FEV1 trajectory; bronchiolitis obliterans syndrome; hematopoietic cell transplantation; outcomes; pulmonary complications.

Figure 1.

Schema of cohort of patients with bronchiolitis obliterans syndrome (BOS) as defined by updated National Institutes of Health (NIH) spirometric criteria. All 36 participants in the fluticasone, azithromycin, and montelukast (FAM) trial were included (11). Only patients with clinically recognized BOS from the Fred Hutchinson Cancer Research Center (FHCRC) retrospective cohort were included. Patients from the FHCRC cohort were excluded for factors that would confound analysis of treatment with FAM on FEV₁ trajectory. ICS = inhaled corticosteroid.

Figure 2.

Trajectory of FEV₁ percent predicted values after allogeneic hematopoietic cell transplant. Bronchiolitis obliterans syndrome (BOS) diagnosis is designated as time 0. Individual trajectories (n = 82) are plotted with a smoothed regression line to illustrate the aggregate trajectory of the entire cohort over time.

Figure 3.

Kaplan-Meier survival estimates at 6-month landmark after bronchiolitis obliterans syndrome (BOS) diagnosis, stratified by tertiles of FVC percent predicted values for the entire cohort (n = 75): upper tertile, greater than 77.5% (black line); middle tertile, 67–77.5% (blue line); and lower tertile, less than 67% (red line). The comparisons are lowest versus highest, hazard ratio (HR) of 2.31 (95% confidence interval [CI], 1.0–5.7; P = 0.06); lowest versus middle, HR of 2.40 (95% CI, 1.0–5.6; P = 0.04); and lowest versus middle/highest, HR of 2.36 (95% CI, 1.2–4.8; P = 0.02).