Preliminary Results of a Phase II Trial of Montelukast for the Treatment of Bronchiolitis Obliterans Syndrome After HSCT

Abstract

Bronchiolitis obliterans syndrome (BOS) after allogeneic HSCT is a deadly manifestation of cGVHD. Current treatments are inferior and yield transient responses with published overall survival of 44% at 2 years. Although the pathogenesis of BOS after HSCT is unknown, a similar disease, BOS after lung transplant is associated with elevated leukotriene levels. We present preliminary results from a prospective, open label, phase II trial testing the efficacy of montelukast, a leukotriene inhibitor, for the treatment of BOS after HSCT. BOS diagnostic criteria included: FEV1<75%, FEV1/VC < 0.7 or air trapping on CT and RV>120% or RV/TLC>120% in the absence of infection and presence of another cGVHD manifestation. Subjects had stable or declining FEV1 on stable or decreasing immunosuppression. Twenty patients have been enrolled. One withdrew prior to treatment and one withdrew after study medication initiation; 16/20 patients have reached the primary endpoint (6 months) on study medication (10 mg qhs). Study participants age ranged from 15-64 years, 12/20 female, with baseline FEV1 from 24 to 73% predicted. All patients met criteria for response on the clinical trial with less than 15% decline in FEV1 % predicted at the primary endpoint. FEV1 increased 5-13% predicted in 5 participants, remained stable in 6 (change <5%), and declined 5-13% in 5. Comparison of patient pre-study FEV1 decline to on-study FEV1 values was generated using the slope of FEV1 volume vs. days post-transplant. The difference in pre- and primary endpoint slope revealed: 14/16 improvement and 2/16 decline. Six minute walk test demonstrated that 4/16 patients had significant increases in walk distance that exceeded the minimally important difference, 2 of which had declining FEV1%. 2/20 had a significant decline in walk test accompanied by a decline in FEV1% predicted. Of 10 patients eligible for the 2 year endpoint, 7/10 are alive with 2 patients with durable FEV1 improvements from baseline (FEV1+ 6%, +14%), 2 stable (FEV1 0%, +1%), 3 with decline from baseline (FEV1 -4%, -4%, -8%). Montelukast was well-tolerated with only one grade II probable attributable adverse event (insomnia) during the six-month collection period. These findings suggest that montelukast is a promising therapy for BOS after allogeneic HSCT.