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
Intervention: Singulair (Montelukast Sodium)
Intervention description: Singulair (Montelukast Sodium):5-10 mg (weight based dosing) by mouth (PO) hour of sleep (HS)
Intervention MeSH terms: Montelukast
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 6 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Leukotriene; Chronic Graft-Versus-Host Disease; Montelukast; Stem Cell Transplant; Bronchiolitis Obliterans

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....
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Age greater than 6 years old.

        Diagnosis of bronchiolitis obliterans after allogeneic or autologous stem cell transplant.
        The criteria will be based on the definitions created by the National Institutes of Health
        (NIH) consortium on chronic graft versus host disease (cGVHD). As part of these criterion,
        for patients without pathologic evidence of BO, one other sign of chronic GVHD must be
        present. For diagnosis of cGVHD, a minimum of the following must be present: 1) a process
        distinct from that diagnosed as acute GVHD, 2) the presence of a diagnostic sign or a
        distinctive sign supported by another clinical or laboratory test, and 3) the exclusion of
        other pathologies (i.e. recurrent cancer, drug reaction or infection (see Appendix 5a for a
        list of diagnostic signs.). To meet criteria for a diagnosis of bronchiolitis obliterans,
        patients must fulfill all 3 criteria. Prior lung tissue biopsy will be analyzed and
        confirmed to show evidence of bronchiolitis obliterans by the National Cancer Institute
        (NCI) Laboratory of Pathology if available. If tissue is not available for confirmation, a
        new biopsy will not be performed.

        For bronchiolitis obliterans:

          1. Forced expiratory volume 1 (FEV1) less than or equal to 75 percent of predicted by
             pulmonary function evaluation for height and weight.

          2. Evidence of air-trapping or small airway thickening or bronchiectasis on high
             resolution chest computed tomography (CT) and residual volume (RV) or RV/forced vital
             capacity (FVC) greater than 120 percent and evidence of chronic GVHD of another organ,
             OR FEV1/ vital capacity (slow or forced VC whichever is larger) ratio less than 5
             percent of predicted for age or less than 0.7, OR pathologic evidence of bronchiolar
             inflammation and obstruction of the lumen consistent with a diagnosis of BO. Pulmonary
             function tests will utilize body plethysmography not helium studies for pertinent
             values when there is a discrepancy if available.

          3. Absence of active infection with appropriate investigation of any clinical symptoms to
             include radiographic, microbiologic, and pathologic studies as determined by the PI or
             LAI.

             Patients must also have 2 PFT measurements with documented FEV1 values greater than 3
             months apart to calculate the entry FEV1 slope. All available prior PFTs will be
             utilized for baseline slope calculation. For adult patients, the absolute FEV1 will be
             utilized for slope calculation; for pediatric patients, the percent predicted will be
             used. For patients enrolled after an acute decline following BMT without 2 post-BMT
             values greater than 3 months apart, the pre-BMT value may be utilized as the first
             value and the entry PFT value may be the second for the slope calculation. The
             baseline and 6th-cycle PFT should be done at the accruing site.

             Prior therapy: For patients with a chronic diagnosis of BO who have been on
             treatments, any prior therapy that has been administered chronically for > 3 months
             will be acceptable for enrollment as long as the patient has not demonstrated
             consistent improvement attributed to these agents in a one month (or more) period of
             observation preceding enrollment. For patients on steroids, a steroid burst exceeding
             and increase of one half mg/kg/day will be considered for the start of the 3 month
             monitoring period. Notably, documented intercurrent infections that are treated with
             antimicrobials that result in improvements to, but not above previous baselines will
             not be considered an improvement attributable to immunosuppressive therapy. Patients
             who have had consistent improvements in the months preceding trial entry will not be
             eligible since there will be no way to discern improvement due to montelukast versus
             another therapy. Alternatively, a patient with a new diagnosis of bronchiolitis
             obliterans characterized by a new decrease in FEV1 is also eligible for this study.
             Notably, patients who have received bronchodilators or other pulmonary therapies may
             be included in this study as long as montelukast is not part of this regimen.

             Performance status: Karnofsky or Lansky performance status greater than or equal to 40
             percent (Appendix 1).

             Ability to give informed consent. For patients less than 18 years of age, their legal
             guardian must give informed consent. Pediatric patients will be included in an age
             appropriate discussion in accordance with NIH guidelines or participating
             institutional guidelines.

             Hepatic function: Patients must have evidence of adequate liver function prior to
             enrollment defined by total bilirubin less than 3 times the upper limit of normal and
             transaminases less than 5 times the upper limit of normal for age appropriate indices.

             Cardiac function: Patients must have evidence of adequate cardiac function prior to
             enrollment defined by ejection fraction greater than 25 percent performed within the
             last 6 months at NIH and absence of symptoms of cardiac disease at FHCRC, JHH, or
             Hackensack.

             Pulmonary function: Patients must have an FEV1 greater than or equal to 20 percent
             predicted for inclusion in this study.

             EXCLUSION CRITERIA:

             Underlying disease status: Patients with tumor burden greater than minimal residual
             disease (i.e. tumor burden that can only be detected by molecular methods) would be
             excluded from this study.

             Prior post-transplant treatment with montelukast or zakirlukast within the past 2
             months and total duration of therapy does not exceed 3 months.

             Clinically significant systemic illness with manifestations of significant organ
             dysfunction which in the judgment of Principal or Associate Investigator would render
             the patient unlikely to tolerate the protocol therapy or complete the study.

             Patients must have been on their current cGVHD therapeutic regimen for at least 3
             months with stable or decreasing FEV1 to be eligible for this trial. Any patient who
             has been on a therapy for less than 3 months for cGVHD will need to be monitored for 3
             months without improvement in FEV1 prior to enrollment.

             Ventilated patients are excluded.

             Patients taking rifampin or phenobarbital as these medications alter the metabolism of
             montelukast.

             Patients taking greater than one age-appropriate dose of ibuprofen or aspirin
             containing products per day that inhibit cyclooxygenase will be excluded from this
             trial. The acceptable upper limit for adult daily doses of aspirin is 650mg/day and
             800mg/day of ibuprophen. For children, the acceptable upper limit of ibuprophen is
             pediatric dose per day (less than 10 mg per kg to a maximum of 800 mg). Children
             should not take aspirin due to risk of Reye's syndrome unless specifically prescribed
             by their physician.

             Patients with a history of allergy to montelukast.

             Pregnant females and nursing mothers will be excluded from this trial due to unknown
             risks to the developing fetus. While on study, patients of child-bearing potential
             must be able to consent to utilize effective birth control measures.