title: 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.
authors.affiliation: Division of Blood and Marrow Transplantation, Children's Research Institute, Children's National Health System, Washington, DC; Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: kmwillia@cnmc.org.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Williams
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Guang-Shing
authors.initials: GS
authors.lastname: Cheng
authors.affiliation: Division of Medicine and Oncology, Washington University, Saint Louis, Missouri.
authors.forename: Iskra
authors.initials: I
authors.lastname: Pusic
authors.affiliation: Division of Hematology/Oncology, Vandebilt University, Nashville, Tennessee.
authors.forename: Madan
authors.initials: M
authors.lastname: Jagasia
authors.affiliation: Division of Hematology/Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Linda
authors.initials: L
authors.lastname: Burns
authors.affiliation: Division of Hematological Malignancies, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.affiliation: Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pidala
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic- Scottsdale, Scottsdale, Arizona.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Palmer
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University, Stanford, California.
authors.forename: Laura
authors.initials: L
authors.lastname: Johnston
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mayer
authors.affiliation: Gilead, Seattle, Washington.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Chien
authors.affiliation: Division of Blood and Marrow Transplantation, Children's Research Institute, Children's National Health System, Washington, DC.
authors.forename: David A
authors.initials: DA
authors.lastname: Jacobsohn
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Steven Z
authors.initials: SZ
authors.lastname: Pavletic
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Martin
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Barry E
authors.initials: BE
authors.lastname: Storer
authors.affiliation: Division of Hematopoietic stem cell transplantation, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Inamoto
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Chai
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Mary E D
authors.initials: MED
authors.lastname: Flowers
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000085:Acetates / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D017963:Azithromycin / Q000627:therapeutic use*; D001989:Bronchiolitis Obliterans / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology / Q000401:mortality; D003521:Cyclopropanes; D018450:Disease Progression; D000068298:Fluticasone / Q000627:therapeutic use*; D005541:Forced Expiratory Volume; D019337:Hematologic Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D011804:Quinolines / Q000627:therapeutic use*; D013440:Sulfides; D016019:Survival Analysis; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D000085:Acetates; D000893:Anti-Inflammatory Agents; D003521:Cyclopropanes; D011804:Quinolines; D013440:Sulfides; D017963:Azithromycin; D000068298:Fluticasone; C093875:montelukast
keywords: Azithromycin; Bronchiolitis obliterans syndrome; Fluticasone; Hematopoietic cell transplantation; Leukotrienes; Lung chronic graft-versus-host disease; Montelukast