Prospective Phase II Trial of Montelukast to Treat Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation and Investigation into Bronchiolitis Obliterans Syndrome Pathogenesis

• Published in: Transplantation and cellular therapy Vol. 28; no. 5; pp. 264.e1 - 264.e9
• Main Authors: Williams, Kirsten M., Pavletic, Steven Z., Lee, Stephanie J., Martin, Paul J., Farthing, Don E., Hakim, Frances T., Rose, Jeremy, Manning-Geist, Beryl L., Gea-Banacloche, Juan C., Comis, Leora E., Cowen, Edward W., Justus, David G., Baird, Kristin, Cheng, Guang-Shing, Avila, Daniele, Steinberg, Seth M., Mitchell, Sandra A., Gress, Ronald E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-05-2022
• Subjects: Acetates - adverse effects; Bronchiolitis obliterans; Bronchiolitis Obliterans - drug therapy; Chronic graft-versus-host-disease; Cyclopropanes; Hematopoietic Stem Cell Transplantation - adverse effects; Humans; Prospective Studies; Quinolines; Sulfides; Syndrome; Transplantation; Chronic graft-versus-host-disease; Bronchiolitis obliterans; Transplantation
• ISSN: 2666-6367; 2666-6367
• DOI: 10.1016/j.jtct.2022.01.021

•Montelukast safely stabilized the majority of patients with established bronchiolitis obliterans syndrome (BOS) post-hematopoietic cell transplantation (HCT).•Improvement in symptoms and function and good 2-year survival occurred in responders.•Our data suggest that leukotrienes play a role in BOS occurring after HCT.
Bronchiolitis obliterans syndrome (BOS) is a severe manifestation of chronic graft-versus-host disease (cGVHD) following hematopoietic cell transplantation (HCT). Montelukast interrupts cysteinyl leukotriene (CysLT) activity and may diminish the activation and homing of cells to bronchioles and subsequent fibrosis. We performed a prospective phase II trial to test whether montelukast altered lung decline for patients with BOS after HCT. In this single-arm, open-label, multi-institutional study, the primary endpoints were stability or improvement (<15% decline) in forced expiratory volume in 1 second (FEV1) and a <1-point decline in the slope of FEV1 after 6 months of treatment. Secondary endpoints included symptom and functional responses and immune correlates investigating the role of leukotrienes in BOS progression. The study enrolled 25 patients with moderate to severe lung disease after 3 months of stable cGVHD therapy. Montelukast was well tolerated, and no patient required escalation of BOS-directed therapy. At the primary endpoint, all 23 evaluable patients met the criteria for treatment success using FEV1% predicted, and all but 1 patient had stable or improved FEV1 slope. In those with a >5% improvement in FEV1, clinically meaningful improvements were seen in the Lee scores of breathing, energy, and mood. Improvements in the Human Activity Profile and 6-minute-walk test were observed in those with a <5% decline in FEV1. Overall survival was 87% at 2 years. Immune correlates showed elevated leukotriene receptor levels on blood eosinophils and monocytes versus healthy controls, elevated urine leukotrienes in 45% of the cohort, and CysLT receptors in bronchoalveolar lavage subsets and a predominance of Th2 cells, all pretreatment. These data suggest that montelukast may safely halt the progression of BOS after HCT, and that leukotrienes may play a role in the biology of BOS.
[Display omitted]