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

Background: Bronchiolitis obliterans syndrome (BOS) is a severe manifestation of chronic graft-versus-host disease (cGVHD) following hematopoietic cell transplantation (HCT). Montelukast interrupts cysteinyl leukotriene activity and may diminish the activation and homing of cells to bronchioles and subsequent fibrosis. Methods: We performed a prospective phase II trial to test whether montelukast altered lung decline for patients with BOS after HCT in a single arm, open-label, multi-institutional study with primary endpoints of: i) FEV1 stability or improvement (<15% decline) and ii) slope of FEV1<1 point decline after six months treatment. Findings: 25 patients enrolled with moderate to severe lung disease after three months of stable cGVHD therapy. Montelukast was well-tolerated and no patient required escalation of BOS-directed therapy. At the primary endpoint, all evaluable patients (n=23) met criteria for treatment success using FEV1% predicted, and all but one had stable or improved FEV1 slope. Secondary endpoints included symptoms, function, and immune correlates. In those with > 5% FEV1 improvement, clinically meaningful improvements were seen in the Lee scores of breathing, energy, and mood, and in the Human Activity Profile, and 6MW for <5% FEV1 decline. Overall survival was 87% at two-years. Immune correlates showed elevated leukotriene receptor levels on blood eosinophils and monocytes vs. healthy controls, elevated urine leukotrienes in 45%, and cysteinyl leukotriene receptors on bronchoalveolar lavage subsets, all pre-treatment. Trial Registration: This study was approved with registration number: NCT00656058. Interpretation: These data suggest that montelukast may safely halt progression of BOS after HCT and that leukotrienes may play a role in the biology of BOS. Funding: NIH, Tucker Foundation, Ben’s Run. Declaration of Interest: KMW, EWC, DGJ, KB, LEC, BMG, FTH, SMS, DEF, DGJ, JR, JCGB, DA, SAM, GSC, REG have no disclosures. SJL reports Research funding: Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer; Syndax, Takeda; Provision of study medication: Janssen; Steering committee for a clinical trial: Incyte; Consulting fees from Mallinckodt, Amgen. SZP reports research funding through the collaborative and clinical trials agreements executed between the NCI CCR and Kadmon, Pharmacyclics, Celgene, Eli Lilly, Actelion, CTI, and Mereo. PJM reports: other from AbGenomics (now AltruBio), personal fees from Pfizer, Inc. , personal fees from Pediatric Transplantation and Cellular Therapy Consortium, personal fees from Genentech, Inc, personal fees from Pharmacyclics, personal fees from Neovii, personal fees from Enlivex Therapeutics, personal fees from Mesoblast, personal fees from Rigel, personal fees from Talaris, personal fees from Janssen, non-financial support from Janssen, personal fees from Mount Sinai School of Medicine, outside the submitted work. Ethical Approval: Patients were prospectively enrolled at Fred Hutchinson Cancer Research Center and National Institutes of Health after obtaining institutional review board approval with informed consent