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. Purpose: We hypothesized that FAM (inhaled Fluticasone, Azithromycin, and Montelukast) with a brief steroid pulse could avert progression of new-onset BOS. Experimental design: We tested this in a phase II, single-arm, open label, multicenter study (NCT01307462). Results: Thirty-six patients were enrolled within 6 months of BOS diagnosis. The primary endpoint was treatment failure, defined as 10% or greater FEV1% decline at 3 months. At 3 months, 6% (2/36, 95% CI 1%–19%) had treatment failure (vs. 40% in historical controls, p<0.001). 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 SF-36 social functioning score and mental component score, FACT 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% CI 21%–54%, n=13/36, with 6 documented failures, 7 missing pulmonary function tests). Overall survival was 97% (95% CI 84%–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.

How I treat bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation

“…For the treatment of new-onset BOS after HCT, a study of inhaled fluticasone, azithromycin, and montelukast (FAM) with brief steroid burst (1 mg/kg per day prednisone) and rapid taper has been reported (0.25 mg/kg per week) (Figure 2). 54 This prospective, multi-institutional study of 36 patients showed stabilization or improvement in 94% of patients at 3 months and overall survival of 97% at 6 months. 54 Based on these results, I initiate FAM therapy for all newly diagnosed patients in addition to continuation or resumption of classical cGVHD therapy with calcineurin inhibitor or sirolimus.…”

“…54 This prospective, multi-institutional study of 36 patients showed stabilization or improvement in 94% of patients at 3 months and overall survival of 97% at 6 months. 54 Based on these results, I initiate FAM therapy for all newly diagnosed patients in addition to continuation or resumption of classical cGVHD therapy with calcineurin inhibitor or sirolimus. The mechanistic rationale for these agents are: inhaled steroids provide local anti-inflammatory effects, azithromycin impairs interleukin-8 (IL-8) production and neutrophilia, and montelukast blocks leukotriene activity, impairing cellular homing and activation and possibly blocking fibroblast proliferation and collagen deposition (Figure 4).…”

Montelukast for Bronchiolitis Obliterans Syndrome After Lung Transplantation: A Randomized Controlled Trial

“…Another single-agent, openlabel study evaluated montelukast in 25 patients with established BOS after allogenic hematopoetic stem cell transplantation and showed stabilization with less than 15% decline in FEV1 for the entire cohort over 6 months of treatment [25]. Also in combination therapy (with fluticasone and azithromycin (FAM) or combination with budesonide/formoterol and n-acetylcysteine), montelukast shows improvement of lung function in patients with BOS after allogenic hematopoetic stem cell transplantation [26,27].…”

Diagnosis and management of bronchiolitis obliterans syndrome following lung or hematopoietic cell transplantation

“…Norman et al [10] reported a prednisonesparing effect of combination therapy with inhaled fluticasone propionate, AZI, and montelukast (FAM) for a case series of eight HCT-BOS recipients compared to 14 historical controls (inhaled fluticasone and montelukast have also been suggested to have potential treatment benefit for BOS in both HCT and/or LTX recipients on the basis of small case series investigations). Williams et al [11] subsequently reported that FAM therapy for a larger cohort of 36 patients enrolled in a single-arm, open-label, multicenter clinical trial was associated with a significantly reduced likelihood of treatment failure (defined as ≥10% decline in FEV1 at 3 months) for the FAM cohort versus historical controls and allowed a substantial reduction in corticosteroid dosing. Additional multi-center, prospective, randomized, placebo-controlled clinical trials (RCTs) are currently underway to better evaluate the efficacy of AZI for HCT-BOS, but results are not yet available.…”