Interim Analysis of a Phase II Trial of Montelukast for the Treatment of Bronchiolitis Obliterans Syndrome After HSCT Reveals Immunobiology of Disease

Bronchiolitis obliterans syndrome (BOS) after allogeneic HSCT is associated with high mortality and unknown pathogenesis. We present interim results from a prospective phase II trial evaluating of montelukast for the treatment of BOS after HSCT and studying BOS biology.  Montelukast interrupts cysteinyl leukotriene activity and may diminish homing of activated cells to bronchioles and fibrosis.  Twenty-three patients have enrolled with stable or decreasing immunosuppression for 3 months prior and BOS diagnosed by modified NIH criteria; 2 were withdrawn, and 19 have completed primary endpoint. Participants ranged from 15-72 years, 13/23 female, most had moderate to severe disease with baseline FEV1 of 46% predicted (24-73), and median FEV1/VC 0.5 (0.29-0.78).  Montelukast was well-tolerated and no patient required escalation of BOS-directed therapy during the evaluation period.  All patients met criteria for treatment success (<15% decline in 6 months), with FEV1 either increased 5-13% of predicted (n=5), stable (n=7), or declined 5-13% (n=6).  FEV1 slope of decline was generated using regression line of FEV1 value vs. days post-HSCT.  At 6 months, slope was improved in 9 patients, stable in 9, declined in 1. Other manifestations of cGVHD showed: 5/8 GI GVHD improved and 3/8 stable; 5/10 liver cGVHD improved, 4/10 stable, 1 worse, using NIH consensus staging.  Survival of the study cohort is 90% (19/21); 2 year survival is 84% (10/12), twice published data (44%).  Bronchoalveolar lavage (BAL) from in non-infected patients at baseline revealed cysteinyl leukotriene receptor expression on CD4 and CD8 T cells, granulocytes, and eosinophils, thereby potentially implicating these populations in BOS biology.  While blood leukotriene receptor expression on CD4 cells was similar to normal donors, CD4 proportion was significantly reduced in BOS patients (p<0.01).  Other blood receptor levels of these populations were similar between normal donors and controls, although CD8 T cells trended toward decreased receptor expression after treatment at 6 months and decreased proportion of CD8 T cells at 2 years (p<0.04).  B cells were absent in BAL while present in blood.  These data suggest that: 1) montelukast is a safe and effective therapy for BOS after allogeneic HSCT; 2) T cells, granulocytes, and eosinophils (though not B cells) were associated with BOS in BAL; and 3) cysteinyl leukotrienes may be a point of regulation in the progression of BOS after HSCT.