Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Post-transplant Events

Influence of oral beclomethasone dipropionate on early non-infectious pulmonary outcomes after allogeneic hematopoietic cell transplantation: results from two randomized trials

Bone Marrow Transplantation volume 45, pages 317–324 (2010)Cite this article

Abstract

Early non-infectious pulmonary complications represent a significant cause of mortality after hematopoietic cell transplantation (HCT). We tested the hypothesis that oral beclomethasone dipropionate (BDP) is effective for preventing early non-infectious pulmonary complications after allogeneic HCT. We retrospectively reviewed the medical records of 120 patients, 60 in each treatment arm, to identify non-infectious and infectious pulmonary events and pulmonary function test results from all patients who participated in two randomized trials of oral BDP for treatment of acute gastrointestinal GVHD. 17-Beclomethasone monopropionate (17-BMP), the active metabolite of BDP, was evaluated in blood from the right atrium in four patients. Thirty-three of 42 (79%) placebo-treated patients experienced a decrease of the DLCO from pretransplant to day 80 after transplant, compared with 27 of 49 (55%) BDP-treated patients (P=0.02). In the first 200 days after randomization, there were no cases of non-infectious pulmonary complications in BDP-treated patients, vs four cases among placebo-treated patients (P=0.04). Levels of 17-BMP were detected in atrial blood at steady state. Delivery of a potent glucocorticoid such as 17-BMP to the pulmonary artery after oral dosing of BDP may be useful in modulating pulmonary inflammation and preventing the development of non-infectious pulmonary complications after allogeneic HCT.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Cordonnier C, Bernaudin JF, Bierling P, Huet Y, Vernant JP . Pulmonary complications occurring after allogeneic bone marrow transplantation. A study of 130 consecutive transplanted patients. Cancer 1986; 58: 1047–1054.

    Article  CAS  PubMed  Google Scholar 

  2. Jules-Elysee K, Stover DE, Yahalom J, White DA, Gulati SC . Pulmonary complications in lymphoma patients treated with high-dose therapy autologous bone marrow transplantation. Am Rev Respir Dis 1992; 146: 485–491.

    Article  CAS  PubMed  Google Scholar 

  3. Clark JG, Hansen JA, Hertz MI, Parkman R, Jensen L, Peavy HH . NHLBI workshop summary. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis 1993; 147 (6 Part 1): 1601–1606.

    Article  CAS  PubMed  Google Scholar 

  4. Afessa B, Tefferi A, Litzow MR, Peters SG . Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 2002; 166: 1364–1368.

    Article  PubMed  Google Scholar 

  5. Afessa B, Tefferi A, Litzow MR, Krowka MJ, Wylam ME, Peters SG . Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 2002; 166: 641–645.

    Article  PubMed  Google Scholar 

  6. Shankar G, Cohen DA . Idiopathic pneumonia syndrome after bone marrow transplantation: the role of pre-transplant radiation conditioning and local cytokine dysregulation in promoting lung inflammation and fibrosis. Int J Exp Pathol 2001; 82: 101–113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cooke KR, Kobzik L, Martin TR, Brewer J, Delmonte Jr J, Crawford JM et al. An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. Blood 1996; 88: 3230–3239.

    CAS  PubMed  Google Scholar 

  8. Clark JG, Madtes DK, Hackman RC, Chen W, Cheever MA, Martin PJ . Lung injury induced by alloreactive Th1 cells is characterized by host-derived mononuclear cell inflammation and activation of alveolar macrophages. J Immunol 1998; 161: 1913–1920.

    CAS  PubMed  Google Scholar 

  9. Della Volpe A, Ferreri AJ, Annaloro C, Mangili P, Rosso A, Calandrino R et al. Lethal pulmonary complications significantly correlate with individually assessed mean lung dose in patients with hematologic malignancies treated with total body irradiation. Int J Radiat Oncol Biol Phys 2002; 52: 483–488.

    Article  PubMed  Google Scholar 

  10. Broliden K . Parvovirus B19 infection in pediatric solid-organ and bone marrow transplantation. Pediatr Transplant 2001; 5: 320–330.

    Article  CAS  PubMed  Google Scholar 

  11. Englund JA, Boeckh M, Kuypers J, Nichols WG, Hackman RC, Morrow RA et al. Brief communication: fatal human metapneumovirus infection in stem-cell transplant recipients. Ann Intern Med 2006; 144: 344–349.

    Article  PubMed  Google Scholar 

  12. Cooke KR, Hill GR, Gerbitz A, Kobzik L, Martin TR, Crawford JM et al. Tumor necrosis factor-alpha neutralization reduces lung injury after experimental allogeneic bone marrow transplantation. Transplantation 2000; 70: 272–279.

    Article  CAS  PubMed  Google Scholar 

  13. Clark JG, Madtes DK, Martin TR, Hackman RC, Farrand AL, Crawford SW . Idiopathic pneumonia after bone marrow transplantation: cytokine activation and lipopolysaccharide amplification in the bronchoalveolar compartment. Crit Care Med 1999; 27: 1800–1806.

    Article  CAS  PubMed  Google Scholar 

  14. Panoskaltsis-Mortari A, Taylor PA, Yaeger TM, Wangensteen OD, Bitterman PB, Ingbar DH et al. The critical early proinflammatory events associated with idiopathic pneumonia syndrome in irradiated murine allogeneic recipients are due to donor T cell infusion and potentiated by cyclophosphamide. J Clin Invest 1997; 100: 1015–1027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hockenbery DM, Cruickshank S, Rodell TC, Gooley T, Schuening F, Rowley S et al. A randomized, placebo-controlled trial of oral beclomethasone dipropionate as a prednisone-sparing therapy for gastrointestinal graft-versus-host disease. Blood 2007; 109: 4557–4563.

    Article  CAS  PubMed  Google Scholar 

  16. McDonald GB, Bouvier M, Hockenbery DM, Stern JM, Gooley T, Farrand A et al. Oral beclomethasone dipropionate for treatment of intestinal graft-versus-host disease: a randomized, controlled trial. Gastroenterology 1998; 115: 28–35.

    Article  CAS  PubMed  Google Scholar 

  17. McDonald GB . Oral beclomethasone dipropionate: a topically active corticosteroid for the treatment of gastrointestinal graft-versus-host disease following allogeneic hematopoietic cell transplantation. Expert Opin Investig Drugs 2007; 16: 1709–1724.

    Article  CAS  PubMed  Google Scholar 

  18. Lung function testing: selection of reference values and interpretative strategies. American Thoracic Society. Am Rev Respir Dis 1991; 144: 1202–1218.

    Article  Google Scholar 

  19. American Thoracic Society. Single-breath carbon monoxide diffusing capacity (transfer factor). Recommendations for a standard technique--1995 update. Am J Respir Crit Care Med 1995; 152 (6 Part 1): 2185–2198.

    Google Scholar 

  20. Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med 1995; 152: 1107–1136.

    Article  Google Scholar 

  21. Crapo RO, Morris AH . Standardized single breath normal values for carbon monoxide diffusing capacity. Am Rev Respir Dis 1981; 123: 185–189.

    CAS  PubMed  Google Scholar 

  22. Crapo RO, Morris AH, Gardner RM . Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis 1981; 123: 659–664.

    CAS  PubMed  Google Scholar 

  23. Freudenberger TD, Madtes DK, Curtis JR, Cummings P, Storer BE, Hackman RC . Association between acute and chronic graft-versus-host disease and bronchiolitis obliterans organizing pneumonia in recipients of hematopoietic stem cell transplants. Blood 2003; 102: 3822–3828.

    Article  CAS  PubMed  Google Scholar 

  24. Fukuda T, Hackman RC, Guthrie KA, Sandmaier BM, Boeckh M, Maris MB et al. Risks and outcomes of idiopathic pneumonia syndrome after nonmyeloablative and conventional conditioning regimens for allogeneic hematopoietic stem cell transplantation. Blood 2003; 102: 2777–2785.

    Article  PubMed  Google Scholar 

  25. Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA . Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985; 312: 152–158.

    Article  CAS  PubMed  Google Scholar 

  26. Fisher L, Van Belle G . Biostatistics: a methodology for the health sciences. Wiley: New York, 1993 xxii, 991 p.pp.

    Google Scholar 

  27. Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18: 695–706.

    Article  CAS  PubMed  Google Scholar 

  28. Kalbfleisch JD, Prentice RL . The statistical analysis of failure time data. Wiley: New York, 1980 xi, 321 p.pp.

    Google Scholar 

  29. Yamaguchi K, Mori M, Kawai A, Takasugi T, Oyamada Y, Koda E . Inhomogeneities of ventilation and the diffusing capacity to perfusion in various chronic lung diseases. Am J Respir Crit Care Med 1997; 156: 86–93.

    Article  CAS  PubMed  Google Scholar 

  30. Crapo RO, Forster RE 2nd Carbon monoxide diffusing capacity. Clin Chest Med 1989; 10: 187–198.

    CAS  PubMed  Google Scholar 

  31. Kantrow SP, Hackman RC, Boeckh M, Myerson D, Crawford SW . Idiopathic pneumonia syndrome: changing spectrum of lung injury after marrow transplantation. Transplantation 1997; 63: 1079–1086.

    Article  CAS  PubMed  Google Scholar 

  32. Crawford SW, Longton G, Storb R . Acute graft-versus-host disease and the risks for idiopathic pneumonia after marrow transplantation for severe aplastic anemia. Bone Marrow Transplant 1993; 12: 225–231.

    CAS  PubMed  Google Scholar 

  33. Weiner P, Azgad Y, Weiner M . Inspiratory muscle training during treatment with corticosteroids in humans. Chest 1995; 107: 1041–1044.

    Article  CAS  PubMed  Google Scholar 

  34. Hildebrandt GC, Olkiewicz KM, Corrion LA, Chang Y, Clouthier SG, Liu C et al. Donor-derived TNF-alpha regulates pulmonary chemokine expression and the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation. Blood 2004; 104: 586–593.

    Article  CAS  PubMed  Google Scholar 

  35. Hildebrandt GC, Olkiewicz KM, Corrion L, Clouthier SG, Pierce EM, Liu C et al. A role for TNF receptor type II in leukocyte infiltration into the lung during experimental idiopathic pneumonia syndrome. Biol Blood Marrow Transplant 2008; 14: 385–396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nestel FP, Price KS, Seemayer TA, Lapp WS . Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease. J Exp Med 1992; 175: 405–413.

    Article  CAS  PubMed  Google Scholar 

  37. Cooke KR, Hill GR, Crawford JM, Bungard D, Brinson YS, Delmonte Jr J et al. Tumor necrosis factor- alpha production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease. J Clin Invest 1998; 102: 1882–1891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hill GR, Crawford JM, Cooke KR, Brinson YS, Pan L, Ferrara JL . Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood 1997; 90: 3204–3213.

    CAS  PubMed  Google Scholar 

  39. Rizzello F, Gionchetti P, D’Arienzo A, Manguso F, Di Matteo G, Annese V et al. Oral beclometasone dipropionate in the treatment of active ulcerative colitis: a double-blind placebo-controlled study. Aliment Pharmacol Ther 2002; 16: 1109–1116.

    Article  CAS  PubMed  Google Scholar 

  40. Rai RM, Hendrix TR, Moskaluk C, Levine DS, Pasricha PJ . Treatment of idiopathic lymphocytic enterocolitis with oral beclomethasone dipropionate. Am J Gastroenterol 1997; 92: 147–149.

    CAS  PubMed  Google Scholar 

  41. Levine DS . Immune modulating therapies for idiopathic inflammatory bowel diseases. Adv Pharmacol 1994; 25: 171–234.

    Article  CAS  PubMed  Google Scholar 

  42. Brogden RN, Pinder RM, Sawyer PR, Speight TM, Avery GS . Beclomethasone dipropionate inhaler: a review of its pharmacology, therapeutic value and adverse effects. I: Asthma. Drugs 1975; 10: 166–210.

    Article  CAS  PubMed  Google Scholar 

  43. Harris DM . Properties and therapeutic uses of some corticosteroids with enhanced topical potency. J Steroid Biochem 1975; 6: 711–716.

    Article  CAS  PubMed  Google Scholar 

  44. Wurthwein G, Rohdewald P . Activation of beclomethasone dipropionate by hydrolysis to beclomethasone-17-monopropionate. Biopharm Drug Dispos 1990; 11: 381–394.

    Article  CAS  PubMed  Google Scholar 

  45. Daley-Yates PT, Price AC, Sisson JR, Pereira A, Dallow N . Beclomethasone dipropionate: absolute bioavailability, pharmacokinetics and metabolism following intravenous, oral, intranasal and inhaled administration in man. Br J Clin Pharmacol 2001; 51: 400–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

H Gary Schoch provided clinical data from a computerized patient database. George McDonald initiated the research and participated in study design, analysis and preparation of the paper. The randomized placebo-controlled trials on which these data are based were supported by Orphan Products Development Grants from the US Food and Drug Administration (FD-R 000827 and FD-R 02599) and by Enteron Pharmaceuticals Inc., a wholly owned subsidiary of DOR BioPharma, Ewing, NJ. This research was supported by grants from the National Institutes of Health, National Cancer Institute (CA18029 and CA15704).

Author information

Authors and Affiliations

  1. Clinical Research Division, Pulmonary, Gastroenterology/Hepatology, and Clinical Statistics Sections, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA, USA,

    J W Chien, M Sakai, T A Gooley, H G Schoch & G B McDonald

  2. Department of Medicine and Biostatistics, University of Washington School of Medicine, Seattle, WA, USA,

    J W Chien, M Sakai, T A Gooley, H G Schoch & G B McDonald

Authors
  1. J W Chien
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T A Gooley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H G Schoch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G B McDonald
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J W Chien.

Additional information

Authors' responsibilities and contributions: Jason Chien analyzed the PFTs, reviewed the clinical pulmonary events, and participated in the analysis of data and preparation of the paper. Miwa Sakai reviewed the patients’ medical records for pulmonary events and participated in data analysis and preparation of the paper. Ted Gooley performed statistical analyses and participated in the preparation of the paper.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chien, J., Sakai, M., Gooley, T. et al. Influence of oral beclomethasone dipropionate on early non-infectious pulmonary outcomes after allogeneic hematopoietic cell transplantation: results from two randomized trials. Bone Marrow Transplant 45, 317–324 (2010). https://doi.org/10.1038/bmt.2009.129

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2009.129

Keywords

Search

Advanced search

Quick links