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

• Type of Material: Article
• Authors: Kirsten Williams, Emory University; Steven Z Pavletic, National Cancer Institute, National Institutes of Health, Bethseda; Stephanie J Lee, Fred Hutchinson Cancer Research Center; Paul J Martin, Fred Hutchinson Cancer Research Center; Don E Farthing, National Institutes of Health, Bethesda; Frances T Hakim, National Institutes of Health, Bethesda; Jeremy Rose, National Institutes of Health, Bethesda; Beryl L Manning-Geist, Memorial Sloan Kettering Cancer Center; Juan C Gea-Banacloche, National Institute of Allergy and Immunology, National Institutes of Health; Leora E Comis, NIH, Bethesda; Edward W Cowen, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethseda; David G Justus, Boston Children’s Hospital; Kristin Baird, National Cancer Institute, NIH, Bethesda; Guang-Shing Cheng, Fred Hutchinson Cancer Research Center; Daniele Avila, National Cancer Institute, National Institutes of Health, Bethesda; Seth M Steinberg, National Cancer Institute, NIH, Bethesda; Sandra A Mitchell, National Cancer Institute, Bethesda; Ronald E Gress, National Institutes of Health, Bethesda
• Language: English
• Date: 2022-05-04
• Publisher: ELSEVIER SCIENCE INC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022 Published by Elsevier Inc. on behalf of The American Society for Transplantation and Cellular Therapy.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jtct.2022.01.021
• Title of Journal or Parent Work: TRANSPLANTATION AND CELLULAR THERAPY
• Volume: 28
• Issue: 5
• Start Page: 264.e1
• End Page: 264.e9
• Keywords: OBSTRUCTIVE LUNG-DISEASE; VERSUS-HOST-DISEASE; Life Sciences & Biomedicine; RISK-FACTORS; Bronchiolitis obliterans; CLINICAL-TRIALS; DIAGNOSIS; T-CELLS; Science & Technology; Transplantation; Chronic graft-versus-host-disease; CONSENSUS DEVELOPMENT PROJECT; Immunology; CHRONIC GVHD; Hematology; BONE-MARROW-TRANSPLANTATION; CYSTEINYL-LEUKOTRIENES

Abstract

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.