Effect of Cyclosporine Inhalation Solution (CIS) on Lung Function and Inflammatory Biomarkers in Patients with Hematopoietic Stem Cell Transplant (HSCT) Associated Bronchiolitis Obliterans Syndrome (BOS)
Authors: Athale Janhavi , Gormley Nicole J , Reger Robert , Alsaaty Sara , Reda Debra , Worthy Tatyana , Saxena Ankit , Tian Xin , Childs Richard W. , Suffredini Anthony F 
Published: November 2019

Background: Chronic graft versus host disease of the lungs may result in bronchiolitis obliterans syndrome (BOS), an inflammatory injury to medium size airways leading to fibrosis. BOS is often treated with an increase in immunosuppression which can be associated with systemic complications (e.g. organ dysfunction, increased susceptibility to infection and blunting of graft versus leukemia effect). In order to provide enhanced local delivery of an immunosuppressant, cyclosporine, we studied the effects of cyclosporine inhalation solution (CIS) in allogeneic hematopoietic stem cell transplant (HSCT) patients with BOS with a short-term assessment of lung function and inflammatory markers in blood and bronchoalveolar lavage (BAL).
Methods: Patients who underwent an allogeneic HSCT meeting the NIH consensus clinical definition of BOS were eligible for inclusion, and were treated with CIS and monitored for treatment response with serial pulmonary function tests (PFTs). At baseline, patients were classified as having stable or progressive disease (i.e. > 10% decline in forced expiratory volume in one second (FEV1) in the preceding 18 weeks). Response was defined as either improvement or stabilization at week 18. Improvement was defined as an increase in FEV1 (regardless of baseline categorization) > 10%. Stabilization was defined as FEV1 increase or decrease < 10% in patients with progressive disease at baseline, and with a reduction in systemic immunosuppression by 25% in those with stable disease at baseline. Patients with declining FEV1 > 10% were classified as non-responders, and patients with FEV1 decline > 20% or with worsening clinical status were taken off protocol. BALs were performed at study entry and week 18 of treatment. BAL and serum samples were analyzed via a custom Luminex® panel. The 37 analytes studied included the following categories: 1) chemokines (CCL2, 3, 5, 18; CXCL5, 9, 10, 13), 2) cytokines (IL-1β, -1ra, -2, -2rα, -6, -7, -8, -10, -12p70, -15, -17a, -23, -17E/25, TNFα, IFNγ), 3) matrix metalloproteinases (MMP1-3, 7-9, 12-13), 4) growth-factors (VEGF-α, G-CSF), and 5) others (PD-L1, surfactant protein D, osteopontin, myeloperoxidase).
Results: In total, 20 HSCT patients with BOS were enrolled (median age 45.5 yrs: range 14-71; 13 men and 7 women), and 11 patients completed the study through week 18. The average time from transplant was 4.6 yrs (range 1-28, median 3 yrs). Baseline FEV1 was 1.18 liters (range 0.5-2.02), and with an average FEV1 of 36% predicted (range 18-56%). At the time of enrollment, 12 patients had stable disease, and 8 had progressive disease. Nine patients discontinued treatment due to either worsening FEV1 by 25% (n=1), relapse of primary disease (n=1), or side effects (n=7; cough and bronchospasm). Sixteen patients were included in the evaluable patient population (patients who received treatment for at least the first two weeks) with 9 responders (4 with improvement, 5 with stabilization) and 7 non-responders. Among those completing the study (n=11), 4 had improvement in FEV1, 5 had stable disease, and 2 were non-responders. Seven patients were continued on CIS through an extended use protocol.
The baseline BAL cell differentials demonstrated a neutrophil predominance (66 + 29 %) that persisted at week 18 (56 + 35%). In the BAL, MMP-7 increased from baseline (150 + 215 pg/mL) to week 18 (1956 + 2624 pg/mL; p value 0.049), while soluble PD-L1 levels fell (97 + 55 pg/mL to 55 + 43 pg/mL; p value 0.04). The other categories of biomarkers in BAL were either undetectable (n = 12) or demonstrated no significant difference (n = 23) in patients with or without a clinical response to CIS. Similarly, concomitant serum biomarkers showed no difference in treatment after CIS, even when classified amongst responders and non-responders.
Conclusion: In HSCT-BOS, CIS led to an improvement or stabilization of PFTs and/or a decrease in systemic immunosuppression in 9 of the 11 patients that completed the study. Due to cough and bronchospasm, only 11 of 20 patients were able to complete treatment through week 18. Inflammatory markers in the serum and BAL were not elevated at baseline or at the end of study. These data suggest that later stages of BOS may represent progression from a state of inflammatory injury to a fibrotic process. Based on our findings, we believe patients with later stage BOS may benefit from investigational therapeutics targeting lung remodeling.
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Disclosures
No relevant conflicts of interest to declare.

OffLabel Disclosure:
Not really. This drug is not commercially available or FDA approved. An IND was obtained for the use of an inhaled formulation of cyclosporine. Aerosolized cyclosporine has been used previously in other patients (lung transplant associated BOS)