Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation

Abstract

Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT) is associated with high mortality. We hypothesized that inhaled fluticasone, azithromycin, and montelukast (FAM) with a brief steroid pulse could avert progression of new-onset BOS. We tested this in a phase II, single-arm, open-label, multicenter study (NCT01307462). Thirty-six patients were enrolled within 6 months of BOS diagnosis. The primary endpoint was treatment failure, defined as 10% or greater forced expiratory volume in 1 second decline at 3 months. At 3 months, 6% (2 of 36, 95% confidence interval, 1% to 19%) had treatment failure (versus 40% in historical controls, P < .001). FAM was well tolerated. Steroid dose was reduced by 50% or more at 3 months in 48% of patients who could be evaluated (n = 27). Patient-reported outcomes at 3 months were statistically significantly improved for Short-Form 36 social functioning score and mental component score, Functional Assessment of Cancer Therapies emotional well-being, and Lee symptom scores in lung, skin, mouth, and the overall summary score compared to enrollment (n = 24). At 6 months, 36% had treatment failure (95% confidence interval, 21% to 54%, n = 13 of 36, with 6 documented failures, 7 missing pulmonary function tests). Overall survival was 97% (95% confidence interval, 84% to 100%) at 6 months. These data suggest that FAM was well tolerated and that treatment with FAM and steroid pulse may halt pulmonary decline in new-onset BOS in the majority of patients and permit reductions in systemic steroid exposure, which collectively may improve quality of life. However, additional treatments are needed for progressive BOS despite FAM.

Keywords: Azithromycin; Bronchiolitis obliterans syndrome; Fluticasone; Hematopoietic cell transplantation; Leukotrienes; Lung chronic graft-versus-host disease; Montelukast.

Figure 1. a and b: FAM stabilizes FEV1 in the majority of patients at 3 months

a) 83% of patients had study-defined documented success on 3 month PFTs, 3% percent had documented failure at 3 months (10% or more absolute decline in percent predicted FEV1) and 5 (14%) were missing 3 month PFTs. These 5 patients were later reclassified as 1 failure (no PFTs available at 2,3 or 6 months) and 4 successes (3 based on 2 month PFTs and 1 on the basis of 2 or 6 month PFTs. b) Proportion of patients (n=30 evaluable at 3 months) with greater or equal to 5% improvement, greater than or equal to 5% decline (and including those who were not able to be evaluated as these failures), or less than 5% change (stability).

Figure 2. Trajectory of FEV1 over time after FAM exposure

Individual percent predicted FEV1 values are graphed as a function of time for each patient. The bold line represents the median of the cohort.