Montelukast to Treat Bronchiolitis Obliterans
Condition: Bronchiolitis Obliterans; Chronic Graft Versus Host Disease; Leukotriene; Montelukast; Stem Cell Transplant
MeSH terms: Bronchiolitis; Bronchiolitis Obliterans Syndrome; Bronchiolitis Obliterans; Graft vs Host Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

      Bronchiolitis obliterans is a form of chronic graft-versus-host disease (GVHD) that sometimes
      develops after stem cell transplantation (SCT) or bone marrow transplantation (BMT).

      In bronchiolitis obliterans, immune cells that normally fight infections attack the lungs of
      the transplant recipient, causing destruction of lung tissue and fibrosis (scarring). When
      fibrosis develops, the lungs cannot work properly.

      Montelukast (Singulair) is a drug that has been used for many years to treat asthma. Its use
      as a treatment for bronchiolitis obliterans is experimental.

      Objectives:

      To see if montelukast improves or stabilizes lung function in patients who develop
      bronchiolitis obliterans after BMT or SCT.

      To assess the safety of montelukast in patients with bronchiolitis obliterans after BMT or
      SCT

      To see if montelukast affects the cells that damage the lungs.

      To see if montelukast improves other forms of chronic GVHD, quality of life, and overall
      survival in patients with bronchiolitis obliterans after BMT or SCT.

      Eligibility:

      Patients 6 years of age and older with bronchiolitis obliterans following stem cell
      transplantation.

      Design:

      Patients take one montelukast tablet daily for 6 months and undergo the following procedures
      during this period:

        -  Lung function tests. The patient breathes into a machine that measures the amount of air
           that goes into and out of the lungs. This test is done once a month for 3 months, then
           at 6 months, 12 months and 24 months.

        -  Medical history and physical examination at the study site about every 3 months for the
           first year of the study and then at 12 months and 24 months. Patients also have physical
           examinations monthly for the first 6 months at their primary doctors office. Tests may
           include blood and urine tests, chest computed tomography (CT) scans, echocardiogram
           (heart ultrasound), 2- and 6-minute walk tests, and quality-of-life questionnaires.

        -  Bronchoalveolar lavage in patients 18 years of age and older. The subject s mouth, nose
           and airways are numbed with lidocaine. Some patients may need sedation or anesthesia for
           the procedure. A tube (bronchoscope) is then passed through the nose into the airway,
           and a small amount of fluid is put into the lung. The fluid is then removed and tested
           for infections or other lung problems.

        -  Apheresis to collect white blood cells. Whole blood is collected through a tube inserted
           into a vein in the arm. The white cells are extracted in a cell separator machine, and
           the rest of the blood is returned to the body through a tube placed in a vein in the
           other arm. The cells are used to study GVHD and bronchiolitis obliterans.

        -  Patients who wish to continue montelukast therapy after 6 months may do so under the
           care of their primary doctor, if both agree to the continuation....
    

Detailed description: 
      Background:

      Bronchiolitis obliterans (BO) is an insidious disease with high mortality following
      allogeneic blood or marrow transplantation (BMT). There are no consistently effective
      treatments for BO following BMT and the pathogenesis is largely unknown.

      The mechanisms underlying similar immune-mediated lung destructive processes are better
      elucidated. Rejection following allogeneic lung transplantation and scleroderma lung disease
      result from analogous immunologically mediated destruction of lung tissue leading to similar
      pathologic and clinical presentations to post-BMT BO.

      Increased leukotriene production has recently been implicated in the development of both
      post-lung transplant BO and scleroderma lung disease in animal models and patient studies.

      Montelukast (singulair) is an approved, well-tolerated, oral agent that inhibits leukotriene
      action in lung inflammation. This agent has been extensively used in children and adults to
      treat asthma with an excellent safety profile.

      Objectives:

      To evaluate if montelukast stabilizes or improves pulmonary function in patients with BO
      after BMT using forced expiratory volume 1 (FEV-1) changes as primary endpoints, and oxygen
      saturation, pulmonary function test (PFT) parameters (forced expiratory flow (FEF) 25-75,
      residual volume (RV) and RV/forced vital capacity (FVC), carbon monoxide diffusing capacity
      (DLC02), FEV-1/FVC, FEV-1/slow vital capacity (SVC) ratio), and timed walk tests as secondary
      endpoints.

      To evaluate the safety of montelukast in the population of patients with BO after BMT.

      To investigate if leukotriene elevation contributes to the pathogenesis of BO after BMT by
      measuring leukotriene levels of the blood, urine, and bronchoalveolar lavage (BAL), and
      leukotriene surface receptor expression on immune cells before and after montelukast
      administration.

      To determine if montelukast improves other chronic graft versus host disease (cGVHD)
      manifestations, quality of life, and overall survival.

      Eligibility:

      Patients greater than or equal to 6 years old with bronchiolitis obliterans following stem
      cell transplantation for any disease indication may be enrolled.

      Design:

      This is a prospective phase II study, the primary aim of which is to assess whether
      montelukast improves or stabilizes the pulmonary function of patients with BO after BMT.

      Primary outcome data will be analyzed in 2 ways. 1) The proportion of patients with stable or
      improved percent predicted of FEV-1 will be compared against benchmark data obtained from a
      literature review. 2) The slope of FEV-1 before and after the introduction of montelukast
      will be compared.

      Pediatric and adult patients with BO following BMT will receive approved doses of montelukast
      continuously.

      The planned length of the study would be 2 years per patient with primary endpoint at 6
      months, permitting sufficient time to determine safety and meet other endpoints.

      This phase II trial will be conducted at 2 institutions: National Institutes of Health (NIH)
      and Fred Hutchinson Cancer Research Center. Forty-five patients will be enrolled on this
      trial.
    

Intervention name(s): Singulair (Montelukast Sodium)
Intervention type(s): Drug
Intervention description(s): Singulair (Montelukast Sodium):5-10 mg (weight based dosing) by mouth (PO) hour of sleep (HS)
Intervention MeSH terms: Montelukast
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Leukotriene; Chronic Graft-Versus-Host Disease; Montelukast; Stem Cell Transplant; Bronchiolitis Obliterans