Clinical trial NCT03072849: Early Detection and Management of Bronchiolitis Obliterans Syndrome Following Pediatric Hematopoietic Stem Cell Transplantation
Official title: Early Detection and Management of Bronchiolitis Obliterans Syndrome Following Pediatric Hematopoietic Stem Cell Transplantation
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Bronchiolitis Obliterans Syndrome
Keywords: Pediatrics
Airflow obstruction
Chronic graft-vs-host disease
Bronchiolitis obliterans syndrome
Lead sponsor: Ann & Robert H Lurie Children's Hospital of Chicago
Sponsor class: OTHER
First posted: 2017-03-07
Enrollment: 23
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Pediatric patients undergoing allogenic hematopoietic stem cell transplant

Brief summary: This study aims to determine whether or not early spirometric detection and management of obstructive lung disease with combined fluticasone/azithromycin/montelukast therapy (FAM) can attenuate declining lung function, prevent the development of bronchiolitis obliterans, and improve patient outcomes following hematopoietic stem cell transplant.

Detailed description: Bronchiolitis obliterans syndrome (BOS) is an inflammatory condition of the lungs that leads to obstructive physiology, irreversible fibrosis of terminal bronchioles, and obliteration of the small airways. In both children and adults, the prevalence of BOS is approximately 6% in those with chronic graft-vs-host disease (cGVHD), although this may be a gross underestimation given current diagnostic guidelines. Once diagnosed, the prognosis is extremely unfavorable. BOS carries a mortality rate of approximately 40-60%, with a five year survival rate of 13%.

Early on, BOS is symptomatically silent. Once symptoms are present, there is a high likelihood of irreversible disease regardless of the combination of immune suppression used. Given these circumstances, early diagnosis is of utmost importance, and can be characterized by an isolated and subclinical decline in lung function. Recent studies have suggested that early decline in lung function on pulmonary function testing (PFT) may be representative of developing BOS.

Due to the lack of consistent screening and diagnostic criteria, many patients with evolving BOS elude a timely diagnosis, thereby jeopardizing their chance of survival. In response, several experts have recommended frequent PFT screening and a modified, less stringent set of diagnostic criteria with the goal of establishing earlier diagnosis and timely intervention.

Traditionally, treatment of BOS has included aggressive immunosuppression, leaving patients at risk for life-threatening invasive infections, multi-system co-morbidities, and the threat of lung transplantation. Recent studies have demonstrated that early management with agents such as inhaled corticosteroids (ICS), macrolides, and leukotriene receptor antagonists (LTRA) can lead to improvements in both lung function and clinical symptoms.

This study aims to evaluate the utility of frequent and routine pulmonary surveillance in pediatric patients who have undergone allogenic HSCT. Our prospective study design provides a novel framework for the implementation of standardized lung function screening every three months in the first two years following HSCT. With this, we hypothesize that standardized PFT screening will improve diagnostic sensitivity and allow for earlier intervention in patients with evolving airway obstruction and BO.

This study also aims to evaluate the efficacy of inhaled fluticasone, azithromycin, and montelukast (FAM therapy) in the management of early airflow obstruction in pediatric patients following allogenic HSCT. Early airflow obstruction is defined by pulmonary function testing (FEV1 decline of ≥10% predicted with a FVC \<0.8). With this, we hypothesize that FAM therapy will attenuate the progression of airflow obstruction and improve lung function in those with irreversible airflow obstruction at one and two years when compared to historical controls.

Eligibility criteria: Inclusion Criteria:

1. Diagnosis: Patients undergoing myeloablative allogenic hematopoietic stem cell transplant for any indication (both malignant and non-malignant) are eligible.
2. Graft: Eligible patients will have one or more of the following donor stem cell sources:

   * Bone marrow
   * Placental blood (umbilical cord blood)
   * Cytokine mobilized peripheral blood
3. Eligible patients will have one of the following sources of donor stem cells:

   * HLA matched family member
   * Partially matched family member (mismatched for a single HLA locus at A, B, C or DR)
   * Fully HLA matched or partially mismatched unrelated marrow or peripheral blood stem cells (per institutional donor selection standards)
   * HLA matched or partially mismatched (at least 4/6 match at A, B, DR) cord blood.
4. Conditioning Regimen: Patients expecting to receive any type of myeloablative HSCT conditioning regimen are eligible.
5. Prior therapies: Patients undergoing stem cell transplant of any kind.
6. Required laboratory parameters: Patients able to adequately perform pulmonary function testing per ATS/ERS guidelines, as determined by the enrolling investigator and trained respiratory therapists.
7. The patient and/or the patient's legally authorized guardian must acknowledge in writing that consent to become a study subject has been obtained in accordance with the institutional policies approved by the U.S. Department of Health and Human Services. Informed consent must be signed prior to registration on study.

Exclusion Criteria:

1. Subjects with a previous solid organ transplant.
2. Recurrent or progressive malignancy requiring anti-cancer therapy.
3. Subjects with evidence of underlying obstructive pulmonary disease prior to transplant (clinical history of asthma or baseline FEV1 \<80% predicted with FEV1/FVC \<80%).
4. Known history of allergy or intolerance to Montelukast, Zafirleukast, Azithromycin, Erythromycin, Clarithromycin, Prednisone, or Sirolimus.
5. Chronic supplemental oxygen requirement or hypoxemia \<92% SpO2.
6. Clinical asthma (variable and recurrent symptoms of airflow obstruction and airway hyper-responsiveness).
7. Pregnancy or nursing: All females of childbearing age must have a negative serum or urine pregnancy test \<7 days before study drug administration.
8. Chronic treatment with any inhaled steroid for \>1 month in past three months.
9. Treatment with montelukast or zafirukast for \>1 month in past three months.
10. Treatment with systemic steroids for \>1 month in past three months.
11. Treatment with any FDA non-approved study medication within the past four weeks. Off label treatment with FDA approved medication is allowed.
12. Evidence of any viral, bacterial, or fungal infection involving the lung and not responding to appropriate treatment.
13. Inability to perform pulmonary function testing (PFT), as determined by the enrolling investigator or PFT lab.
14. Any condition that, in the opinion of the enrolling investigator, would interfere with the subject's ability to comply with the study requirements.

Primary outcomes:
measure: Lung function
timeFrame: 2 years
measure: Survival
timeFrame: 2-4 years
Secondary outcomes:
measure: Risk factor assessment
timeFrame: 2 years
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Ann & Robert H Lurie Children's Hospital of Chicago
state: Illinois
Study officials:
References:
citation: Chien JW, Martin PJ, Gooley TA, Flowers ME, Heckbert SR, Nichols WG, Clark JG. Airflow obstruction after myeloablative allogeneic hematopoietic stem cell transplantation. Am J Respir Crit Care Med. 2003 Jul 15;168(2):208-14. doi: 10.1164/rccm.200212-1468OC. Epub 2003 Mar 20.
citation: Bergeron A, Belle A, Chevret S, Ribaud P, Devergie A, Esperou H, Ades L, Gluckman E, Socie G, Tazi A. Combined inhaled steroids and bronchodilatators in obstructive airway disease after allogeneic stem cell transplantation. Bone Marrow Transplant. 2007 May;39(9):547-53. doi: 10.1038/sj.bmt.1705637. Epub 2007 Mar 12.
citation: Bashoura L, Gupta S, Jain A, Couriel DR, Komanduri KV, Eapen GA, Safdar A, Broglio KR, Adachi R, Dickey BF. Inhaled corticosteroids stabilize constrictive bronchiolitis after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2008 Jan;41(1):63-7. doi: 10.1038/sj.bmt.1705877. Epub 2007 Oct 15.
citation: Kaya Z, Weiner DJ, Yilmaz D, Rowan J, Goyal RK. Lung function, pulmonary complications, and mortality after allogeneic blood and marrow transplantation in children. Biol Blood Marrow Transplant. 2009 Jul;15(7):817-26. doi: 10.1016/j.bbmt.2009.03.019.
citation: Norman BC, Jacobsohn DA, Williams KM, Au BK, Au MA, Lee SJ, Moravec CK, Chien JW. Fluticasone, azithromycin and montelukast therapy in reducing corticosteroid exposure in bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: a case series of eight patients. Bone Marrow Transplant. 2011 Oct;46(10):1369-73. doi: 10.1038/bmt.2010.311. Epub 2010 Dec 6.
citation: Hildebrandt GC, Fazekas T, Lawitschka A, Bertz H, Greinix H, Halter J, Pavletic SZ, Holler E, Wolff D. Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transplant. 2011 Oct;46(10):1283-95. doi: 10.1038/bmt.2011.35. Epub 2011 Mar 28.
citation: Pulsipher MA, Skinner R, McDonald GB, Hingorani S, Armenian SH, Cooke KR, Gracia C, Petryk A, Bhatia S, Bunin N, Nieder ML, Dvorak CC, Sung L, Sanders JE, Kurtzberg J, Baker KS. National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplantation Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: the need for pediatric-specific long-term follow-up guidelines. Biol Blood Marrow Transplant. 2012 Mar;18(3):334-47. doi: 10.1016/j.bbmt.2012.01.003. Epub 2012 Jan 14.
citation: Majhail NS, Rizzo JD, Lee SJ, Aljurf M, Atsuta Y, Bonfim C, Burns LJ, Chaudhri N, Davies S, Okamoto S, Seber A, Socie G, Szer J, Van Lint MT, Wingard JR, Tichelli A; Center for International Blood and Marrow Transplant Research; American Society for Blood and Marrow Transplantation; European Group for Blood and Marrow Transplantation; Asia-Pacific Blood and Marrow Transplantation Group; Bone Marrow Transplant Society of Australia and New Zealand; East Mediterranean Blood and Marrow Transplantation Group; Sociedade Brasileira de Transplante de Medula Ossea. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Bone Marrow Transplant. 2012 Mar;47(3):337-41. doi: 10.1038/bmt.2012.5.
citation: Gassas A, Craig-Barnes H, Dell S, Doyle J, Schechter T, Sung L, Egeler M, Palaniyar N. Chest health surveillance utility in the early detection of bronchiolitis obliterans syndrome in children after allo-SCT. Bone Marrow Transplant. 2013 Jun;48(6):814-8. doi: 10.1038/bmt.2012.228. Epub 2012 Nov 19.
citation: Prais D, Sinik MM, Stein J, Mei-Zahav M, Mussaffi H, Steuer G, Hananya S, Krauss A, Yaniv I, Blau H. Effectiveness of long-term routine pulmonary function surveillance following pediatric hematopoietic stem cell transplantation. Pediatr Pulmonol. 2014 Nov;49(11):1124-32. doi: 10.1002/ppul.22944. Epub 2013 Nov 4.
citation: Madanat-Harjuoja LM, Valjento S, Vettenranta K, Kajosaari M, Dyba T, Taskinen M. Pulmonary function following allogeneic stem cell transplantation in childhood: a retrospective cohort study of 51 patients. Pediatr Transplant. 2014 Sep;18(6):617-24. doi: 10.1111/petr.12313. Epub 2014 Jul 7.