ronchiolitis obliterans is an obstructive disease of the small airways of the lung that may develop after either hematopoietic stem cell or lung transplantation. It is associated with considerable morbidity and mortality in long-term transplant survivors and thus represents a major impediment to the success of these therapies Mortality due to bronchiolitis obliterans-associated respiratory failure may occur in more than 55% of patients developing this complication typically within 3 to 5 years following transplantation. The pathogenesis of bronchiolitis obliterans in hematopoietic stem cell and lung transplants appears to share a common final pathway of immune-mediated injury and inflammation to airway epithelium and sub-epithelial structures that results in granulation tissue and fibro-proliferation. Following hematopoietic stem cell transplantation, a chronic inflammatory process develops as a consequence of transplanted T cells targeting allo-antigens expressed on the respiratory epithelium of the recipient. In contrast, the inflammatory injury that develops in the transplanted lung results from alloimmune-dependent and independent mechanisms. Other additive factors to these immune-based inflammatory injuries include viral infections and micro-aspiration. Treatment is based primarily on increased systemic immunosuppression which results in attendant increased risk of infection and morbidity. As a consequence, conventional therapy for bronchiolitis obliterans has not improved long-term outcome of this disorder. Recently, cyclosporine inhalation solution (CIS: made by the APT pharmaceutical company) in solution with propylene glycol has been shown to improve overall survival and chronic rejection-free survival in lung transplant patients. These findings suggest targeted delivery of immunosuppressive therapy to the diseased organ warrants further investigation as this may minimize the morbidity associated with systemic immunosuppression. However, inhaled cyclosporine has not been studied in the treatment of BO following hematopoietic stem cell transplantation. This program represents collaboration between the Hematology branch of the NHLBI, The Critical Care Medicine Department of the NIH Clinical Center, and The Pulmonary Medicine Department at The University of Maryland. Studies are being done in association Aldo Iacono, MD, the Medical Director of the Lung Transplant Program at the University of Maryland. Dr. Iacono pioneered the development of inhaled cyclosporine for lung transplants. Our group was awarded a bench to bedside award to study the safety and efficacy of inhaled cyclosporine for the treatment of BO. Two distinct patient populations will be offered enrollment on this clinical protocol: hematopoietic transplant recipients with BO and lung transplant recipients with BO referred from the University of Maryland. Patients will undergo dose titration of inhaled cyclosporine to a maximum dose of 300mg, three times weekly. Clinical parameters, including pulmonary function tests, will be measured in addition to laboratory markers of the anti-inflammatory response to CIS measured in the blood and from bronchio-alveolar lavages. Adverse events associated with treatment will be recorded. The primary objective is assessing the safety and efficacy of inhaled cyclosporine as a new therapy in hematopoietic transplant patients and lung transplant patients with established BO and to promote a better understanding of the pathogenesis of BO in these two transplant groups. This study is actively accruing patients with preliminary efficacy having already been observed in the first cohort of stem cell transplant patients being treated with this agent.Preliminary data have shown that Inhaled cyclosporine can be delivered safely and can stabilize or improve lung function in HSCT recipients with severe BOS, allowing systemic immunosuppression to be reduced. To date, we have found that use of local, targeted therapy with CIS resulted in minimal systemic absorption compared to typical oral administration, and achieved high drug levels in the lung tissue as demonstrated by the lung deposition results. Although the trial is ongoing, proof of principle that patients with BOS post transplant can have an improvement in their lung function following CIS treatment has already been demonstrated on this study.

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7
Fiscal Year
2016
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U.S. National Heart Lung and Blood Inst
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Ahn, Inhye E; Farooqui, Mohammed Z H; Tian, Xin et al. (2018) Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. Blood 131:2357-2366
Lee, JongBok; Minden, Mark D; Chen, Weihsu C et al. (2018) Allogeneic Human Double Negative T Cells as a Novel Immunotherapy for Acute Myeloid Leukemia and Its Underlying Mechanisms. Clin Cancer Res 24:370-382
Buchan, Alice; Merideth, Melissa A; Childs, Richard W et al. (2018) Novel management of vaginal chronic graft-versus-host disease causing haematometra and haematocolpos. BMJ Case Rep 2018:
Etzion, Ohad; Takyar, Varun; Novack, Victor et al. (2018) Spleen and Liver Volumetrics as Surrogate Markers of Hepatic Venous Pressure Gradient in Patients With Noncirrhotic Portal Hypertension. Hepatol Commun 2:919-928
Allan, David S J; Cerdeira, Ana Sofia; Ranjan, Anuisa et al. (2017) Transcriptome analysis reveals similarities between human blood CD3- CD56bright cells and mouse CD127+ innate lymphoid cells. Sci Rep 7:3501
Pantin, Jeremy; Purev, Enkhtsetseg; Tian, Xin et al. (2017) Effect of high-dose plerixafor on CD34(+) cell mobilization in healthy stem cell donors: results of a randomized crossover trial. Haematologica 102:600-609
Scrivani, Claire; Merideth, Melissa A; Klepac Pulanic, Tajana et al. (2017) Early Diagnosis of Labial Fusion in Women After Allogeneic Hematopoietic Cell Transplant Enables Outpatient Treatment. J Low Genit Tract Dis 21:157-160
McDuffee, E; Aue, G; Cook, L et al. (2017) Tumor regression concomitant with steroid-refractory GvHD highlights the pitfalls of PD-1 blockade following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 52:759-761
Purev, Enkhtsetseg; Tian, Xin; Aue, Georg et al. (2017) Allogeneic transplantation using CD34(+) selected peripheral blood progenitor cells combined with non-mobilized donor T cells for refractory severe aplastic anaemia. Br J Haematol 176:950-960
van Besien, Koen; Childs, Richard (2016) Haploidentical cord transplantation-The best of both worlds. Semin Hematol 53:257-266

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