Encouraging Results of a Phase II Trial of Inhaled Fluticasone Propionate, Azithromycin, and Montelukast (FAM) May Maintain Lung Function in Bronchiolitis Obliterans Syndrome (BOS) after Hematopoietic Cell Transplantation

Background: Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplant (HCT) is associated with high mortality.  Recently, we showed efficacy for montelukast to treat BOS.  We hypothesized that FAM (Fluticasone proprionate (440 mcg inhaled bid, provided by GlaxoSmithKline), Azithromycin (250 mg 3x/week), and Montelukast (10mg QD, provided by Merck) for up to 6 months, with brief steroid pulse could avert progression of new-onset BOS and tested this in a phase II, single-arm, open label, multicenter study (NCT01307462).  Results: Thirty-six patients from 10 institutions were enrolled within 6 months of BOS diagnosis (NIH modified criteria: FEV1<75% predicted, FEV1/VC <0.7, and >10% FEV1 decline from pre-HSCT, absence of infection).  The median age was 57 years (range 23-72), 47% were females, with moderate obstruction (median FEV1 46%; FEV1/FVC 0.5) at enrollment.  The primary endpoint was treatment success, defined as < 10% FEV1 decline at 3 months, with 60% treatment success seen in historical controls (published data). FAM was well tolerated with only 1 grade 4 SAE possibly related to FAM (infection), and no patient stopped FAM prior to 3 months.  3 month results: Eighty-three percent (n=30/36) had treatment success (vs. 60% in historical controls, p=0.004) at 3 months; 5 lacked pulmonary function tests (PFTs), and 1 had decline. Assuming patients without PFTs at 3 months were treatment failures, 36% (n=13/36) had increased FEV1 by 5% or more, and 33% (n=12/36) had less than 5% decline in FEV1. Steroid exposure was reduced significantly from a median of 0.65 mg/kg/day at enrollment to 0.31 mg/kg/day at 3 months in evaluable patients, with only 19% receiving added immunosuppression during that period (associated with <20% of successes). Based on NIH calculated overall cGVHD response, 19% had a CR or PR, while 22% had stable disease at 3 months. Patient-reported outcomes (n=24) were better from baseline to 3 months for SF-36 social functioning score (p=0.03) and mental component score (p=0.02), FACT emotional well-being (p=0.03), and Lee symptom scores in lung (p=0.01), skin (p=0.03), mouth (p=0.03), and overall summary score (p=0.001).  Six minute walk test improved by a median of 127 feet (p=0.02).  6 month results: 10 patients could not be evaluated at 6 months: 1 died, 1 withdrew, 5 did not undergo PFTs and 3 were on study < 6 months; 20/26 (77%) evaluable patients had treatment success at 6 months.  Overall survival at 6 months was 97% (n=35/36). Conclusion: These data suggest that: FAM was well tolerated and may halt pulmonary compromise in newly diagnosed BOS and permit steroid reductions, which collectively improve cGVHD outcomes and quality of life.

Figure. Change in individual and mean percentage FEV1% over time