Characterization of Spirometric Response to Standard-of-care Treatment in Lung Allograft Recipients With Bronchiolitis Obliterans and the Utility of Spirometric Criteria for Rescue Therapy: Implications for the Design of Risk-stratified Clinical Trials

Abstract

Background: The spirometric response to standard-of-care (SOC) immunosuppressive therapy for the management of bronchiolitis obliterans syndrome (BOS) has been sparsely reported in the literature. Data from a Medicare-approved Registry were analyzed to characterize the effectiveness/durability of a wide range of SOC interventions to manage the decline of lung function and to validate the study spirometric criteria for initiation of rescue therapy.

Methods: Lung transplant recipients with refractory BOS at 21 US collaborating centers were enrolled in the Registry. Data included both nonspirometric (eg, demographic, Immunosuppressive Regimens for management of BOS) and spirometric parameters (ie, forced expiratory volume in 1 s [FEV 1 ] measurements and derived indices). The utility of study FEV 1 criteria for treatment (ie, statistically significant rate of FEV 1 decline >30 mL/mo) was evaluated by comparing the spirometric course between participants who met or did not meet this criterion.

Results: Only 21% of participants treated with SOC therapy had >50% decrease (76 ± 25% decrease) in the rate of FEV 1 decline. Although 51% of participants had a partial response (rate of FEV 1 decline decreased on average 71%), 49% of participants had a substantial increase (mean increase 224%). The FEV 1 criterion for treatment was able to identify 19% of participants (48/258) who achieved durable stabilization (ie, nonsignificant rate of FEV 1 <30 mL/mo) with SOC therapy.

Conclusions: Patients with BOS have a widely variable response to SOC therapy. Our findings support the use of FEV 1 rate of decline to assess response to SOC therapy and to ensure appropriate assignment of participants with refractory BOS to rescue therapy treatment cohorts.

FIGURE 1.

Enrollment into the Registry. At enrollment, participants were segregated on the basis of FEV₁ criteria (ie, <–30 mL/mo, P<0.05). Participants were then segregated on the basis of meeting (AE FEV₁ criteria met) vs not meeting (AE FEV₁ criteria not met) FEV₁ criteria AE. Similarly, participants who initially did not meet AE FEV₁ criteria were segregated on the basis of either meeting (PE FEV₁ criteria met) vs not meeting FEV₁ criteria PE (PE FEV₁ criteria not met). AE, at enrollment; FEV₁, forced expiratory volume in 1 s; PE, post-enrollment.

FIGURE 2.

Box whisker plots showing the rate (mL/mo) of FEV₁ decline in participants who met criteria obtained at 3 separate time points (BOS Dx, AE, and within 2 d after the first ECP treatment), with values expressed as mean and SD detailed at the bottom of the graph. AE, at enrollment; BOS, bronchiolitis obliterans syndrome; Dx, diagnosis; ECP, extracorporeal photophoresis; FEV₁, forced expiratory volume in 1 s.

FIGURE 3.

The relationship of FEV₁ rate of decline (mL/mo) and slope difference (ie, first ECP – BOS Dx) values (y-axis) as related to FEV₁ rate of decline (mL/mo) at BOS Dx (x-axis) in participants who met FEV₁ criteria AE (black circles) vs participants who met FEV₁ criteria PE (red triangles). Linear regression was used to generate predictive lines for each cohort (ie, red line for participants who met FEV₁ criteria PE vs black line for participants who met FEV₁ criteria AE). The green horizontal line demarcates a decrease in the rate of FEV₁ decline (response: +ve value; above green line) vs an increase in the rate of decline (no response: –ve value; below green line). The percentage of participants and the percent change in FEV₁ rate of decline are summarized within the figure for participants who met FEV₁ criteria AE relative to either a response (+ difference values) or a 50% response. AE, at enrollment; BOS, bronchiolitis obliterans syndrome; Dx, diagnosis; ECP, extracorporeal photophoresis; FEV₁, forced expiratory volume in 1 s; PE, post-enrollment.

FIGURE 4.

The indirect relationship between the PC in FEV₁ rate of decline between 2 time points (BOS Dx and within 2 d after the first ECP) vs the time (in days) from BOS diagnosis until the first ECP for participants who met FEV₁ criteria AE (n = 103). The horizontal red line represents the cutoff for response, defined as >50% decrease in the rate of FEV₁ decline, with 22 of 103 cases depicted below the red line. AE, at enrollment; BOS, bronchiolitis obliterans syndrome; Dx, diagnosis; ECP, extracorporeal photophoresis; FEV₁, forced expiratory volume in 1 s; PC, percent change.

FIGURE 5.

The degree of increase in the FEV₁ rate of decline (mL/mo) between the 2 time periods (BOS Dx to left; within 2 d of the first ECP treatment to right) in nonresponders to SOC therapy (ie, <50% drop in the rate of FEV₁ decline). BOS, bronchiolitis obliterans syndrome; Dx, diagnosis; ECP, extracorporeal photophoresis; FEV₁, forced expiratory volume in 1 s; SOC, standard of care.

FIGURE 6.

The degree of decrease in the FEV₁ rate of decline (mL/mo) between the 2 time periods (BOS Dx to left; within 2 d of the first ECP treatment to right) in responders to SOC therapy (ie, >50% drop in the rate of FEV₁ decline). BOS, bronchiolitis obliterans syndrome; Dx, diagnosis; ECP, extracorporeal photophoresis; FEV₁, forced expiratory volume in 1 s; SOC, standard of care.