Multi-Institutional Prospective Phase II Study of Montelukast for the Treatment of Bronchiolitis Obliterans Following Allogeneic or Autologous Stem Cell Transplantation in Children and Adults

Inclusion 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 NIH consortium on 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 NCI Laboratory of Pathology if available. If tissue is not available for
confirmation, a new biopsy will not be performed.

For bronchiolitis obliterans:

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 CT and RV or RV/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.