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Bronchiolitis Obliterans Syndrome (BOS) is a late pulmonary complication of both lung and HSCT resulting in obstructive lung disease. For the latter, BOS is thought to be a manifestation of chronic graft versus host disease (cGVHD). The mainstay of therapy is systemic immunosuppression, which increases the risk of infection and reduces graft versus tumor effects. We investigated whether targeted, local delivery of inhaled cyclosporine could improve or stabilize lung function in BOS patients.
HSCT and lung transplant recipients with BOS were eligible if they met the following inclusion criteria: FEV1<75% predicted, FEV1 decline >10% compared to pre-transplant FEV1, no evidence of pulmonary infection as causative etiology, and one of the following: FEV1/FVC ratio <70%, air-trapping seen on CT scan or RV ≥120%, or evidence of cGVHD affecting at least one other organ system. Subjects received cyclosporine inhalation solution (CIS) 150 mg via nebulizer 3 times weekly for 6 weeks before dose escalation to 300mg three times weekly. Pharmacokinetic and lung deposition studies were performed. The primary endpoint was change in FEV1 at study completion (average of week 18 and 19) compared to study baseline.
16 subjects have been enrolled (median age: 45 years; range: 14-73); 14 had HSCT-associated BOS, and 2 had lung-transplant-associated BOS. The median time from BOS diagnosis to study enrollment was 9 months (range: 2-37). The median FEV1 at study entry was 1.1 liters (range: 0.5-2.11). One patient suffered a severe adverse event with CIS (cough, bronchospasm, and dyspnea requiring hospitalization). Adverse events associated with CIS occurred in 11/12 patients and included grade 2 (range 1-3) cough, bronchospasm, and dyspnea that occurred primarily during inhalation.
Of the 12 evaluable subjects, 4 subjects went off-study (patient choice) prior to completion of the 18 weeks, and were considered non-responders. Responses were observed in 5/10 subjects (50%) with BOS following HSCT. Among responding patients who had an improvement in their FEV1, 3 were also able to decrease their systemic steroid dose (Figure 1). The median peak systemic absorption of cyclosporine was 99 mcg/L (range: 32-263) 20 minutes post-CIS inhalation. Lung deposition studies showed the total deposited dose averaged 13% (range: 4-20 %) of the inhaled dose. Of note, 5 subjects who showed a clinical benefit on study were subsequently enrolled onto a CIS extension protocol.
Conclusion: These data are the first to establish that CIS is safe and can stabilize or improve lung function in HSCT recipients with severe BOS, allowing systemic immunosuppression to be reduced. Importantly, lung deposition studies revealed substantial delivery of CIS could be achieved in the airways with only minimal systemic absorption.
Figure 1. FEV1 and prednisone dose for Subject 8A and 14A
