Montelukast to Treat Bronchiolitis Obliterans

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.

- 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.